Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma

Abstract

Purpose: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.

Patients and methods: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m²/day i.v., 5 days per week for 4 weeks, then 10 MU/m²/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.

Results: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).

Conclusions: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

Figure 1:

Representative H&E slide images of a pathologic complete response (A) and pathologic non-response (B).

Figure 2:. Kaplan-Meier plots of overall survival (A) and recurrence free survival (B).

A. The median follow-up time for OS is 37.87 months (33.2–43.47). Median OS has not been reached. B. The median follow-up time for RFS is 29.17 months (17.27–36.8). Median RFS has not been reached.

Figure 3:

Treatment is associated with a significant increase in CD8+ T cells (A), T regulatory (B) and myeloid cells (C) in the TME.

Figure 4:

Treatment is associated with a profound increase in PD-1 (A) and PD-L1 expression (B) in non-tumor cells, and an increased PD-1/PD-L1 interaction score (C).

Figure 5:

Treatment is associated with decreased PD-1+TIM-3+ CD8 (A) and CD8 T cells (B).

Figure 6:

pCR is associated with increased PD-1+ expression (A), a higher PD-1/PD-L1 interaction score (B) and higher HLA-DR expression (C) in non-tumor cells at baseline.