Published OnlineFirst May 17, 2010; DOI: 10.1158/1078-0432.CCR-10-0505 Cancer Therapy: Clinical Clinical Cancer Research Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells Robert H. Vonderheide1, Patricia M. LoRusso2, Magi Khalil1, Elaina M. Gartner2, Divis Khaira3, Denis Soulieres4, Prudence Dorazio5, Jennifer A. Trosko1, Jens Rüter1, Gabriella L. Mariani6, Tiziana Usari6, and Susan M. Domchek1 Abstract Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer. Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with ex- emestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics. Results: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxi- cities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for ≥12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells. Conclusions: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive ad- vanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade. Clin Cancer Res; 16(13); 3485–94. ©2010 AACR. Therapeutic blockade of the CTL-associated antigen 4 Interaction of CTLA4 with its target ligands (CD80 and (CTLA4, also known as CD152), which is expressed on CD86) results in a negative regulatory signal that limits the surface of activated T cells, represents a promising T-cell activation (4, 5). Monoclonal antibodies (mAb) that and novel approach for the treatment of cancer (1–3). bind to CTLA4 and block its ligand interactions have been shown to enhance and prolong T-cell activation in murine Authors' Affiliations: 1Abramson Cancer Center, University of and human model systems (1). When combined with Pennsylvania, Philadelphia, Pennsylvania; 2Barbara Ann Karmanos antitumor therapies such as chemotherapy, radiation ther- Cancer Institute, Wayne State University, Detroit, Michigan; 3Dedicated apy, vaccine therapy, and many other types of therapy, Clinical Research, Sun City, Arizona; 4Hopital Notre-Dame du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada; blocking anti-CTLA4 mAb can achieve tumor regression 5Pfizer Global Research & Development, New London, Connecticut; in animal models (1). and 6Pfizer Global Research & Development, Milan, Italy Tremelimumab is a fully human IgG2 anti-CTLA4 mAb Note: Supplementary data for this article are available at Clinical Cancer that blocks the binding of CTLA4 to CD80 and CD86, and Research Online (http://clincancerres.aacrjournals.org/). enhances human T-cell activation (6, 7). As a single agent, Although now at new address, G.L. Mariani was affiliated with Pfizer, Inc. tremelimumab has shown antitumor activity in patients during the conduct and analysis of this study. with advanced melanoma, yielding durable (>180 d) objec- Presented in part at the 45th Annual Meeting of the American Society of ∼ Clinical Oncology, May 29 to June 2, 2009, Orlando, FL. Abstract 3034. tive responses in 10% of patients, with the most common adverse events (AE) being diarrhea, rash, and fatigue (6–10). Corresponding Author: Robert H. Vonderheide, 551 BRB II/III, 421 Curie Boulevard, Abramson Cancer Center, University of Pennsylvania, Phila- In a randomized phase III study, however, tremelimumab delphia, PA 19104. Phone: 215-573-4265; Fax: 215-573-2652; E-mail: alone was not found to be superior to chemotherapy in [email protected]. advanced stage melanoma (11). It is generally accepted that doi: 10.1158/1078-0432.CCR-10-0505 combination therapy will be needed to achieve maximum ©2010 American Association for Cancer Research. clinical benefit with anti-CTLA4 mAb (2). www.aacrjournals.org 3485 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst May 17, 2010; DOI: 10.1158/1078-0432.CCR-10-0505 Vonderheide et al. (3-10 mg/kg) of tremelimumab were investigated in com- Translational Relevance bination with the standard dose of exemestane. This study represents the first to explore the use of tremelimumab in Blockade of the immune inhibitory molecule CTL- patients with breast cancer. associated antigen 4 (CTLA4) on T cells represents a promising and novel approach for the treatment of Materials and Methods cancer. Here, we provide the first report of administer- ing the anti-CTLA4 monoclonal antibody (mAb) tre- Study population melimumab to patients with breast cancer. In a Postmenopausal women with histologically or cytolog- phase I study of tremelimumab in combination with ically documented estrogen receptor+ and/or progesterone exemestane, treatment-related diarrhea, pruritus, con- receptor+ breast carcinoma who had relapsed after previ- stipation, and fatigue were commonly observed, but ous treatment for metastatic disease were eligible. Patients at the maximum tolerated dose, there was no grade 3 with metastatic breast cancer of unknown receptor status or 4 treatment-related diarrhea, emphasizing the im- who had previously demonstrated an objective response portance of dose and schedule for safely delivering to hormonal therapy were also eligible. Patients were al- anti-CTLA4 mAb. Stable disease was the best clinical lowed to have either measurable or nonmeasurable dis- response in 42% of patients. Treatment was associated ease. Eligible patients had an Eastern Cooperative with T-cell activation, as revealed by an increase in in- Oncology Group performance status of ≤1; life expectancy – ducible costimulator expressing T cells in blood and a of >6 months; and adequate bone marrow, hepatic, and re- – marked increase in the ratio of inducible costimulator nal function [absolute neutrophil count of ≥1.5×109/L, pla- positive T cells to FoxP3+ regulatory T cells. Under- telets of ≥100 × 109/L, hemoglobin of ≥10 g/dL, total standing the immunologic effect of CTLA4 blockade bilirubin of ≤1.5 × upper limit of normal (ULN), aspartate in humans should facilitate the development of anti- transaminase and alanine aminotransferase of ≤2.5 × ULN CTLA4 mAbs as novel therapeutics for patients with or ≤5 × ULN if liver metastases were present, serum creati- cancer. nine of ≤1.5 × ULN, and serum alkaline phosphatase of ≤2.5 × ULN] ≤2 weeks before treatment. Patients who had received immunotherapy for cancer within 4 weeks before screening or who had received prior Hormonal therapy, particularly for patients with breast doses of any anti-CTLA4 compound were excluded. In ad- cancer, may be well suited for combination with immune dition, patients were excluded if they had a history of therapy, including combination with anti-CTLA4 mAb. chronic inflammatory or autoimmune disease, had chron- Unlike chemotherapy, hormonal therapy is not thought ic or acute viral hepatitis (B or C), required or had poten- to be immunosuppressive, and antitumor T-cell responses tial requirement for systemic corticosteroids, had a to tumor antigens released as a result of response to hor- bleeding disorder or active infection, or had a history with- monal therapy are more likely to be active. Blocking in the last 5 years of autoimmune colitis or other chronic CTLA4 with an anti-CTLA4 mAb may further drive T-cell gastrointestinal condition associated with diarrhea or responses against the tumor. Exemestane is a steroidal ar- bleeding. Patients with any coexisting malignancies, except omatase inhibitor that binds irreversibly to aromatase, for basal or squamous cell carcinoma of the skin or other causing the suppression of aromatase activity in peripheral solid tumors curatively treated with no evidence of disease and tumor tissues, and substantial lowering of serum es- for ≥ 5 years, were also excluded from study participation. trogen levels. Exemestane monotherapy in postmenopaus- This study was conducted according to the Declaration al women with advanced or metastatic breast cancer of Helsinki and relevant International Conference on Har- results in an improved response rate compared with ta- monization Good Clinical Practice guidelines, and with moxifen in the first line setting (12). In women who have approval from the local Institutional Review Boards of progressed on tamoxifen, exemestane therapy results in an participating study sites and the Food and Drug Adminis- improvement in time to progression compared with me- tration (BB-IND 10096; sponsor, Pfizer Corp.). All partici- gestrol