Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study

Abstract

Purpose: To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).

Patients and methods: CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.

Results: Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.

Conclusion: Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

Trial registration: ClinicalTrials.gov NCT02243579.

Figures

FIG 1.

(A) Best change from baseline in skin by modified Severity Weighted Assessment Tool (mSWAT) scoring. Bar color reflects global response according to global response criteria. (B) Representative images showing response in tumor stage (top) and erythrodermic disease (bottom). (C) Longitudinal change from baseline skin mSWAT score. (D) Time to response and response duration. AE, adverse event; M, mycosis fungoides; S, Sézary syndrome.

FIG 2.

Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS).

FIG 3.

(A) Change in skin modified Severity Weighted Assessment Tool (mSWAT) scoring for patient 17 with transient skin flare reaction. (B) Mass cytometry analysis of programmed cell death protein 1 (PD-1) expression of peripheral blood Sézary cells at baseline for 12 patients by skin flare status. (C) Histogram of PD-1 expression of peripheral blood Sézary cells for 12 patients.

FIG 4.

(A) Programmed cell death protein ligand 1 (PD-L1) expression in baseline skin biopsy specimens by immunohistochemistry by response status. (B) Representative images of biopsy specimens with low (top) and high (bottom) PD-L1 intensity. (C) T-cell–inflamed interferon-γ (ΙFN-γ)–related gene expression profiling (GEP) signature scores in baseline skin biopsy specimens by response status. (D) Summary of whole-exome sequencing (WES) results, with selected genomic events displayed. (E) Tumor mutation burden determined by WES by response status. LCT, large-cell transformation; MF, mycosis fungoides; SS, Sézary syndrome.