Neoadjuvant Immune Checkpoint Blockade Has Antitumor Activity

Patients with stage III melanoma who also harbor macroscopic lymph node metastases have poor outcomes; however, adjuvant immune checkpoint blockade monotherapy with either the anti-CTLA4 antibody ipilimumab or the anti–PD-1 antibody nivolumab confers survival benefit to these patients, and treatment with nivolumab plus ipilimumab has been shown to achieve better responses than nivolumab alone in patients with stage IV melanoma, albeit with significant toxicity. Recently, it has been shown that neoadjuvant therapy is at least as efficacious as adjuvant therapy, enhances response monitoring, and enables the use of pathologic complete response (pCR) as a surrogate endpoint in patients with breast cancer. To determine whether neoadjuvant immunotherapy may exhibit similar advantages and also enhance tumor-specific T-cell responses compared to adjuvant immunotherapy, Blank and colleagues evaluated the safety, feasibility, and efficacy of neoadjuvant versus adjuvant nivolumab plus ipilimumab in 20 patients with metastatic stage III melanoma. The primary endpoints were the level and diversity of the neoantigen-specific T-cell response, safety, and feasibility. Treatment-related adverse events occurred in all 20 patients, with treatment-related grade 3–4 adverse events occurring in 90% (9/10 patients treated with neoadjuvant immune checkpoint blockade and 9/10 patients treated with adjuvant immune checkpoint blockade). Of the 9 evaluable patients in the neoadjuvant arm, 3 exhibited pCRs, 3 exhibited near-pCRs, and 1 exhibited a pathologic partial response. T-cell repertoire analysis revealed that neoadjuvant nivolumab plus ipilimumab increased both the magnitude and the diversity of tumor-resident T-cell clones to a greater extent than adjuvant nivolumab plus ipilimumab. Taken together, these results indicate that neoadjuvant nivolumab plus ipilimumab achieves high response rates in patients with metastatic melanoma and support the further investigation of alternative dosing regimens to mitigate the toxicity of this therapy.

Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:1655–61.

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