Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma

Abstract

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses over adjuvant treatment 1 ; however, optimal regimens have not been defined. Herein, we report results from a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs), and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results are the first to describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…Early-stage LUSC patients also revealed immune marker mutation profiles based on their somatic mutational burdens, which may justify a personalized immunotherapeutic approach to target cancers at early stages of disease progression (247). Immunotherapy had been also employed as an intervention in the adjuvant and neoadjuvant settings, the former of which is based on the premise that immunotherapy will enable host immunity's recognition of the tumor-specific antigens (248)(249)(250)(251). In early-stage NSCLC patients, nivolumab administration prior to surgery activated a pathological response in 45% of the tumors studied, which, in turn, increased density of T cell clones in the tumor compartment as well as in the periphery (251).…”

Adjuvant and neoadjuvant treatment of melanoma

“…This has even led to the formation of an International Neoadjuvant Melanoma Consortium which has recently published consensus-based recommendations on neoadjuvant systemic therapy [19]. Treatment approaches with both targeted (BRAF/MEK inhibitor combination) and immunotherapy have been investigated in the neoadjuvant setting [20][21][22][23][24][25]. The treatment duration before surgery typically ranged from 3 to 12 weeks in these trials, frequently followed by a period of adjuvant treatment resulting in a total treatment duration of 1 year.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…However, recent data from murine xenograft models of a neoadjuvant treatment setting show promising effects of immunotherapy on survival in the latter yet non-metastatic setting [193]. Checkpoint inhibitor treatment alone exhibited favorable survival rates in neo-adjuvantly treated melanoma, NSCLC, and glioblastoma cohorts [194][195][196]. Potentially, a reservoir of antigen of the primary tumor may be needed for the induction of strong adaptive immune responses which then exerts its effect on distant micro-metastasis once the primary tumor is removed.…”