Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma

Abstract

Purpose: Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)-naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1-naïve advanced melanoma.

Patients and methods: PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival.

Results: Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%.

Conclusion: Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1-naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

Fig 1.

(A) Treatment exposure and response duration by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; investigator assessed; n = 43). The length of each bar corresponds to the duration of time patients received treatment (in months). Response symbols represent status at first report and at most recent review. (B) Radiographic change of tumor burden from baseline (investigator assessed per RECIST v1.1; n = 43). Two patients had ongoing responses after treatment discontinuation for grade 4 treatment-related adverse events (dashed gray lines). (C) Maximal change in tumor size from baseline (investigator assessed per RECIST v1.1; n = 43). Bar length reflects maximal decrease/increase in size of target lesion(s). Bar color reflects best overall response. irAE, immune-related adverse events.

Fig 2.

Survival of patients with programmed death-1–naïve melanoma in KEYNOTE-020: (A) progression-free survival; (B) overall survival. Percentages are the proportion of patients with survival at that time point. Numbers of patients at risk at each time point are shown below the x-axis.

Fig 3.

(A) Gene expression profile (GEP) scores for patients at pre-treatment timepoint by response status. GEP scores based on data from 16 patients classified by current response (left) and best response RECIST v1.1 (right). (B) Subject-level GEP scores on treatment by best overall response status. On-treatment GEP scores based on data from 14 patients. In all patients, GEP scores were significantly greater on-treatment compared to baseline (1-sided P value 0.049). Response is classified as best overall response and calculated using RECIST v1.1. CR, complete response; PR, partial response; pt, patient; EOT, end of treatment; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; Scr, screening.

Fig A1.

(*) Phase IB/II Study of Pembrolizumab With PEG-IFN in PD-1 Naïve Melanoma: Study Schema.

Fig A2.

Progression-free survival of patients treated in KEYNOTE-020 by prior receipt of IFN (N = 43).

Fig A3.

Progression-free survival of patients treated in KEYNOTE-020 by prior receipt of ipilimumab (N = 43).

Fig A4.

Evaluation of CD8+ T cell infiltrates and PD-L1 expression in tumor samples. (A) T-cell analyses by IHC on pre- and on- treatment tumor samples (N = 21); (B) Pre-treatment PD-L1 staining by IHC on pre- and on- treatment tumor samples (N = 15). Response is classified as best overall response. CR, complete response; IHC, immunohistochemistry; NR, non-responder; PD, progressive disease; PR, partial response; R, responder; SD, stable disease.

Fig A5.

(A) Baseline radiographic tumor burden (RTB) in all patients (N = 43). Total RTB was greater in responders compared to non-responders (left, P = 0.08). Patients with higher liver disease burden were more likely to be non-responders, whether liver tumor burden was considered alone (middle, P = 0.0518) or as a fraction of the total tumor burden (right, P = 0.0731). (B). Higher RTB was associated with shorter PFS and OS, even after controlling for LDH and disease sub-stage. LDH, lactate dehydrogenase; LN, lymph node; NR, non-responder; OS, overall survival; PFS, progression-free survival; R, responder; RTB, radiographic tumor burden; SD, stable disease; ULN, upper limit of normal.