Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma

Abstract

Purpose: Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.

Patients and methods: In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine.

Results: Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab.

Conclusion: In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.

Trial registration: ClinicalTrials.gov NCT01176461.

Fig 1.

(A) The upper row shows computed tomography (CT) scan images of the neck of a patient in cohort 4 who received ipilimumab at 3 mg/kg (pre ipi) and who experienced progression at week 12 with multiple subcutaneous lesions shown at the arrows (pre PD-1). Regression of disease occurred after six doses of nivolumab at 3 mg/kg at week 12 (post PD-1 week 12) and further regression at week 24 (post PD-1 week 24). The lower row shows CT scan images of the thorax of a patient in cohort 2 who received nivolumab 1 mg/kg (pre PD-1 ab) at baseline and who experienced progression at week 12 with increased pleural disease shown at the arrows (post PD-1 ab). There was significant regression of pleural and lung disease after four doses of ipilimumab at 3 mg/kg off protocol at week 12 (post ipi week 12) and further regression at week 24 (post ipi week 24). (B) Bar graphs indicating proportion of patients that are responders (blue bars) or nonresponders (yellow bars) using positive staining cutoffs of 1% or 5% tumor cells with membranous staining of 100 tumor cells counted to define programmed death-ligand 1 (PD-L1) status. Examples of zero staining and ≥ 1% and ≥ 5% positive staining of tumor cells are also shown in the near right column of three micrographs, with corresponding control images with isotype control staining shown in the far right column of three micrographs. Results for a total of 44 patients with available specimens are shown. CR, complete response; PD-1, programmed death-1; PR, partial response.

Fig 2.

Baseline tetramer staining of CD8⁺ (A) NY-ESO-1_157-165– and (B) MART-1_26-35–specific T cells as a percentage of total CD8 T cells on the ordinate, and response plus stable disease versus progression on the abscissa for 45 patients. (C) Changes from baseline to week 12 in tetramer staining of MART-1_26-35–specific T cells as a percentage of total CD8 T cells on the ordinate, with responder plus stable disease versus progression on the abscissa for 37 patients. (D) Dot plots showing CD4⁺/CD25⁺/CD127^lowFoxP3⁺ T regulatory cells (T_regs) as a percentage of total CD4 T cells on the ordinate, with responder plus stable disease versus progression on the abscissa.

Fig A1.

Gating strategy and representative tetramer staining profile for NY-ESO-1_157-165 antigen-specific T cells. Percent positive staining as defined in Patients and Methods by flow cytometry is shown on the ordinates, and mean fluorescence intensity is shown on the abscissas. Initial gating was on forward scatter (FSC) and side scatter (SSC) and then on CD45⁺ T lymphocytes; dead cells were then gated out, as were CD4⁺, CD14⁺, CD19⁺, and CD56⁺ cells, with gating then on CD3⁺CD8⁺ T cells that were tetramer specific. “A” and “W” represent two channels on the flow cytometer. APC-A, allophycocyanin-A; FITC-A, fluorescein isothyocyanate–A; PerCP, peridinin-chlorophyll proteins.