A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

Omid Hamid, Henrik Schmidt, Aviram Nissan, Laura Ridolfi, Steinar Aamdal, Johan Hansson, Michele Guida, David M Hyams, Henry Gómez, Lars Bastholt, Scott D Chasalow, David Berman, Omid Hamid, Henrik Schmidt, Aviram Nissan, Laura Ridolfi, Steinar Aamdal, Johan Hansson, Michele Guida, David M Hyams, Henry Gómez, Lars Bastholt, Scott D Chasalow, David Berman

Abstract

Background: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.

Methods: In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.

Results: Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.

Conclusions: Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.

Figures

Figure 1
Figure 1
Dosing and testing schedule: CA184-004. *Tumor biopsy was performed at baseline and 24 to 72 hours after the second dose of ipilimumab. †Influenza/pneumococcal booster administered 5 days after first dose of ipilimumab. Q3W: every 3 weeks; Q12W: every 12 weeks.
Figure 2
Figure 2
CONSORT diagram: study CA184-004. *Mandatory TA. CONSORT: Consolidated Standards of Reporting Trials; ICF: informed consent form; PD: progressive disease; TA: tumor assessment; W: study week.
Figure 3
Figure 3
Tumor tissue samples from patients with malignant melanoma treated with ipilimumab. 60× images of skin (A, B, F, Subject 04055; E, Subject 04024) and soft tissue (C, Subject 04066; D, Subject 04002) involved with metastasis and infiltration of melanoma cells, respectively. (A-B) Skin under the epidermis stained with hematoxylin and eosin (H&E) before (A) and after (B) treatment with ipilimumab. Melanoma cells are characterized by abundant cytoplasm, large and central nuclei, apparent nucleolus (large arrows). In contrast, melanin pigment (star) is associated with mononuclear leukocytes (small arrows). Note the increase in tumor-infiltrating mononuclear leukocytes (TILs) post-treatment (B) relative to the baseline (A) in this clinical benefit subject. (C-D) FoxP3 positive staining (with anti-FOXP3) of the nuclei of mononuclear leukocytes (small arrows) in a clinical benefit subject at baseline (D). Non-clinical benefit subject (C) shows no staining of mononuclear leukocytes at baseline. (E-F) IDO expression (anti-IDO staining) at baseline in a clinical benefit subject (F) shows staining of mononuclear leukocytes (small arrows), and spindloid and endothelial cells (large arrows). IDO expression is minimal in the non-clinical benefit subject (E) at baseline, showing focal and weak staining of melanoma cells (red arrow). H&E scores for tumor-associated infiltrating mononuclear leukocytes: (A) ≤ 50%, (B) > 50%. Staining scores for FoxP3: (C) 0, (D) 1. Staining scores for IDO: (E) 0, (F) 1.

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