Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable metastatic melanoma: a pilot biomarker-driven trial

Abstract Neoadjuvant immune checkpoint inhibitors (ICIs) improve event-free survival in metastatic melanoma, yet resistance and recurrence remain common. Here we evaluated pepinemab, a Semaphorin 4D (SEMA4D)–blocking antibody, in combination with anti-PD1 nivolumab and/or anti-CTLA4 ipilimumab in a pilot biomarker-driven neoadjuvant trial (NCT03769155) for patients with resectable metastatic melanoma. The primary endpoint was to determine if pepinemab combined with ICIs modulates phenotypic properties within the tumor microenvironment in a manner that enhances T effector cell infiltration. Secondary endpoints included safety and tolerability, pathological response rates and radiographical response. Patients received two neoadjuvant doses followed by curative-intent surgery and one year of adjuvant nivolumab. Pepinemab-containing regimens demonstrated manageable toxicity profiles and did not delay or preclude curative-intent surgical resection in the 38 patients treated. The trial met its primary endpoint, as enrichment of transcripts associated with activated dendritic cells and immune recruitment pathways was observed in tumors from patients receiving pepinemab-containing regimens. Further, immune remodeling was evident by formation of mature lymphoid aggregates resembling tertiary lymphoid structures that contained clonally expanded T cell receptor repertoires. While this study was not powered to assess clinical efficacy, our findings do support further evaluation of SEMA4D blockade as a strategy to modulate the tumor microenvironment and potentially augment immunotherapy in melanoma and other solid malignancies.