Background: We have shown that the pharmacodynamic immune response to anti-PD1 therapy peaks at 3 weeks in the peripheral blood and correlates with tumor burden (Nature 2017). These observations suggest that the presence of antigen is important in the generation of an immune response to checkpoint blockade. We hypothesized that neoadjuvant administration of anti-PD1 therapy followed by complete resection at 3 weeks and adjuvant therapy would be a safe and clinically effective approach for patients with high risk resectable melanoma.

Methods: We enrolled patients with resectable Stage IIIB/C or Stage IV melanoma, who received one 200mg dose of pembrolizumab followed by curative intent resection 3 weeks after Cycle 1 Day 1. Pathologic assessment was performed at the three-week resection timepoint. Patients continued to receive one year of adjuvant pembrolizumab.

Results: 30 patients have been consented since study activation in 2015. 27 patients were eligible to be enrolled and have received treatment before a data cutoff of 12/21/17. 56% of patients were stage IIIC/IV; the remainder were IIIB. 59% were male. Grade 3 adverse events occurred in six patients, with no grade 4 events and no delays in surgical management. No patients were unresectable at the time of surgery. Among 20 patients with at least one year of follow-up or a recurrence event, the 1 year recurrence-free survival (RFS) was 55%. Of the 9 patients who had recurrences, 5 are now disease free after additional therapy or resection and 2 patients remain alive with disease. 2 patients have died. After one dose of pembrolizumab, 8 of 27 (30%) of patients had a complete or-near complete (<10% viable tumor) pathologic response, all of whom are currently recurrence-free. Patients with residual viable tumor of less than 50% at time of resection had a 1 year RFS of 88%, compared to 33% for those with greater than 50% residual viable tumor. Patients with brisk TILs had a 1 year RFS of 89% compared to 27% with non-brisk TILs. Clinical responses after one dose of therapy could also be observed by FDG PET/CT imaging by 3 weeks and correlated with the degree of pathologic response. In addition, a significant increase in CD8 T cells and PD-L1 expression was observed in paired pre and on treatment tissue specimens consistent with an adaptive immune response.

Conclusion: Neoadjuvant anti-PD1 therapy is safe and active in patients with resectable high risk stage III and IV melanoma. Four of five patients with stage IIIB (80%) and seven of 14 with IIIC (50%) melanoma who received neoadjuvant and adjuvant pembrolizumab were recurrence free at 1 year suggesting promising clinical activity and further research is warranted. Consistent with our published data in the peripheral blood, the clinical activity of anti-PD-1 therapy occurs early in the tumor and can be detected by gross, histologic, radiographic, and immune changes after only 1 dose of therapy.

Citation Format: Alexander C. Huang, Xiowei Xu, Robert J. Orlowski, Sangeeth M. George, Lakshmi Chilukuri, Andrew Kozlov, Mary Carberry, Lydia Giles, Suzanne McGettigan, Kristin Kreider, Jennifer H. Yearley, Lakshmanan Annamalai, Gerald Linette, Ravi K. Amaravadi, Lynn M. Schuchter, Michael Farwell, John Wherry, Giorgos Karakousis, Tara Gangadhar. Safety, activity, and biomarkers for neoadjuvant anti-PD-1 therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT181.