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

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. 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. 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. 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. Versluis et al. examine disease recurrence after initial pathologic response to neoadjuvant immune checkpoint inhibition in stage III melanoma. As no genetic changes in the tumor cells mediating immune evasion are found, it is proposed that disease recurrence may potentially be explained by diminishing of the initial therapy-induced immune response. Pathologic response (response assessed in the pathological specimen) to neoadjuvant therapy (treatment before surgery) in patients with melanoma (a type of skin cancer) with lymph node metastases (stage III) usually predicts good long-term outcomes. However, disease recurrence still occurs in a small number of patients. To understand why, patients with such disease recurrence after initial pathologic response were analyzed. Patient data and tumor characteristics such as DNA, RNA, and immune characteristics were assessed. No genetic changes were found that would indicate the tumor cells had developed ways to escape the immune system. This could indicate that the recurrence of the disease was not due to immune evasion, but rather incomplete removal of all tumor cells and weakening of the induced tumor immune response, allowing tumor cells to regrow.