The Oncologist, Vol. 13, No. suppl_4, 10-15, October 2008; doi:10.1634/theoncologist.13-S4-10
© 2008 AlphaMed Press
Overcoming Immunologic Tolerance to Melanoma: Targeting CTLA-4 with Tremelimumab (CP-675,206)
Antoni Ribas
Divisions of Hematology-Oncology and Surgical-Oncology, University of California at Los Angeles, Los Angeles, California, USA
Key Words. CTLA-4 • Melanoma • T cell • Antibody • Tremelimumab • CP-675,206
Correspondence: Antoni Ribas, M.D., Division of Hematology-Oncology, 11-934 Factor Building. UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90095-1782, USA. Telephone: 310-206-3928; Fax: 310-206-0914: e-mail: aribas{at}mednet.ucla.edu
Received December 10, 2007;
accepted for publication February 11, 2008.
Disclosure: The author discloses that this article discusses experimental use of tremelimumab (Pfizer) and ipilimumab (Medarex/Bristol-Myers Squibb). A.R. has received research funding and honoraria from Pfizer. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.
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ABSTRACT
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Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade therapies have been evaluated in clinical trials and have shown promise as possible options for treating patients with cancer. One agent under investigation is tremelimumab (CP-675,206), a monoclonal antibody that has been demonstrated to be a safe and efficacious treatment in patients with malignant melanoma. Results of a phase I clinical trial suggested that a dose of 15 mg/kg of tremelimumab would be the maximum-tolerated dose, with the most common grade 3–4 toxicities being diarrhea and rash. Pharmacokinetic studies showed that the postinfusion plasma concentration and area under the plasma disposition curve both increased in an approximately proportional manner with dose. Studies also showed that tremelimumab has a low clearance (0.132 ml/h·kg), a small volume of distribution (81.2 ml/kg), and a long terminal-phase half-life (22.1 days). A pivotal phase II clinical trial assessing single-agent tremelimumab as second-line therapy in metastatic melanoma has completed accrual, with response rate as the primary endpoint. A pivotal phase III trial has also completed accrual; that study compared the overall survival of previously untreated patients receiving single-agent tremelimumab versus dacarbazine or temozolomide.
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INTRODUCTION
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Tremelimumab (CP-675,206; previously, ticilimumab) is a fully human IgG2 antibody that has a subnanomolar affinity for binding to human cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). It was generated at Abgenix (Fremont, CA) using xenomice for Pfizer, Inc. (New York), the developer of this antibody. Preclinical in vitro studies showed that tremelimumab prevents the binding of CTLA-4 to B7 ligands at subnanomolar concentrations, which results in T-cell activation [1, 2]. In vitro studies demonstrated that the minimal efficacious concentration is 10–30 µ/ml. Another fully human monoclonal antibody, ipilimumab, also is currently under investigation for the treatment of cancers, including melanoma. This paper describes the key clinical trials that provide evidence for the use of tremelimumab in patients with malignant melanoma.
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PHASE I/II CLINICAL EXPERIENCE
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Tremelimumab was evaluated in an open-label, phase I dose-escalation clinical trial [3]. This was the first-in-human study of a single, i.v. infusion of tremelimumab. The primary objective of the study was to determine the maximum-tolerated dose (MTD) of tremelimumab, and the secondary objectives were to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of tremelimumab [3].
To be included in the trial, patients had to have solid malignancies, with no restriction on histology, and either (a) metastatic cancer, with or without measurable lesions and irrespective of prior treatment; or (b) completely resected cancer at high risk for recurrence (>50%) in the adjuvant setting. In both cases, prior therapy had to have been completed 4 weeks before study enrollment. Patients also had to have an estimated life expectancy of at least 6 months and adequate bone marrow and hepatic and renal function. Exclusion criteria included a history of, or significant evidence of a risk for, chronic inflammatory or autoimmune disease, the use of systemic corticosteroids, a history of chronic colitis, or active brain metastases [3]. The presence of bronchial asthma also was added later to the exclusion criteria based on data associating this condition with a polymorphism in the CTLA4 gene [4].
Patients received i.v. tremelimumab at one of seven doses (0.01, 0.1, 1, 3, 6, 10, or 15 mg/kg); those receiving 0.01, 0.1, or 1 mg/kg could re-enter the trial at a higher dose level after they had completed their study follow-up period without unacceptable toxicity [3]. The MTD per protocol specification was 10 mg/kg, but 15 mg/kg also was considered because the dose-limiting toxicities (rash and diarrhea) were not life-threatening with routine medical management. At least three patients were entered in each cohort, and additional patients were enrolled in case of dose-limiting toxicities or to further define the effects of tremelimumab [3].
Patients receiving >1 mg/kg were monitored for subacute autoimmune phenomena for 6–8 weeks before they were enrolled in the next dose-level group [3]. Patients who received the study drug and had measurable disease assessed at baseline and at least once during the study were considered assessable for response. Nonpreviously irradiated lesions that could be accurately measured in two perpendicular dimensions with a minimum size of 2.0 cm x 2.0 cm with conventional techniques or 1.0 cm x 1.0 cm with spiral computed tomography scan were considered measurable lesions [3].
In total, 39 patients were enrolled; of these, 27 were men and 12 were women. The median age was 54 years (range, 30–78 years) [3]. Despite the protocol being open to all histologic diagnoses of cancer, the study investigators focused on entering patients with metastatic melanoma, a cancer type that was hypothesized to be more likely to respond to immune manipulation. Thirty-four patients (87%) had melanoma, and 28 of 35 patients (80%) with metastatic disease had visceral metastasis [3]; 27 patients (69%) had stage IV measurable disease [3]. The lung was the most common site of metastasis (n = 23), followed by the lymph nodes (n = 19), and liver and s.c. tissues (n = 9 for each) [3]. Prior treatments were cytokine therapy (n = 26), chemotherapy (n = 18), radiation therapy (n = 15), other immunotherapy (n = 15), and surgery only (n = 2).
Tremelimumab was given to four patients (10%) in the adjuvant setting, to 11 patients (28%) as front-line therapy for metastatic disease, and to 24 patients (62%) as second-line or greater therapy for metastatic disease [3]. Table 1 presents the number of patients in each dose-level group and the toxicities reported for each cohort. Because three of the six patients receiving the 15-mg/kg dose experienced dose-limiting toxicities (dermatitis and diarrhea), the MTD was determined to be 10 mg/kg [3]. Dermatitis most often presented as a pruriginous maculopapular erythema that developed within 2 weeks of dosing and lasted for <1 month; diarrhea was watery without blood or leukocytes, presented within 2 weeks, and lasted for 2–3 weeks [3]. Asymptomatic elevations of amylase, lipase, and liver enzymes were reported among patients receiving 10 mg/kg and 15 mg/kg [3]. Pre-existing vitiligo worsened in two patients, and another patient developed de novo vitiligo. One patient developed asymptomatic autoimmune thyroiditis with elevated antithyroidglobin and antithyroid peroxidase antibodies, which normalized within 1 month; however, the patient later developed hypothyroidism that required chronic replacement therapy. In general, with the exception of hypothyroidism and vitiligo, toxicities resolved within weeks without corticosteroids or other immune suppressants, and neither cytokine release syndrome nor hypersensitivity reactions were observed [3].
Results showed favorable outcomes with tremelimumab therapy. Four patients experienced objective antitumor responses; of these, two patients experienced a complete response (CR) after dosing with tremelimumab and two patients experienced a partial response (PR) [3]. At the time of publication, all patients continued to be melanoma free, between 50 and 62 months from the original dose of tremelimumab. In addition, four patients who were classified as having stable disease as their best overall response and five patients who were classified as having stable disease or progressive disease at the end of the study evaluation underwent surgical resection of residual lesions, which was followed by long periods of disease-free survival [3].
Pharmacokinetic studies showed that the postinfusion plasma concentration and area under the plasma disposition curve (AUC) both increased in an approximately proportional manner with dose [3]. The clearance of tremelimumab was observed to be low (0.132 ml/h·kg), the volume of distribution was small (81.2 ml/kg), and the terminal-phase half-life was long (22.1 days). Moreover, there was no pharmacokinetic evidence of human antihuman antibodies (HAHA), nor were HAHAs detected by immunoassay [3].
Analysis of these data from patients with melanoma showed a statistically significant relationship between efficacy as measured as clinical benefit response and systemic exposure to tremelimumab measured both as AUC (p = .015) and plasma concentration of tremelimumab 4 weeks postdosing (p = .006) [3]. The predicted probability of experiencing a clinical benefit response without exposure to tremelimumab is 0.077 (90% confidence interval [CI], 0.020–0.247), whereas in this study, at the highest AUC value, the predicted probability was 0.843 (90% CI, 0.184–0.992). In this trial, the target plasma concentration of tremelimumab at 4 weeks postdosing was 30 µ/ml; nearly all patients who experienced a clinical benefit response had a plasma concentration greater than this target value [3]. Finally, although 10 mg/kg was the protocol-defined MTD, the authors recommended that higher dose levels be further explored, because higher plasma levels correlated with antitumor responses and toxicities associated with higher doses resolved without using immunosuppressant therapy in this single-dose clinical trial [3].
Tremelimumab was further evaluated in a phase I/II trial of repeated monthly doses that was conducted among patients with histologically confirmed stage IIIc (unresectable) or stage IV recurrent metastatic melanoma and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 1 [5]. The first part of the trial was a phase I, open-label, multidose study (3, 6, and 10 mg/kg) and a phase I expansion cohort for patients who were HLA-A2.1+; cohorts of three to eight patients received a dose escalation of tremelimumab at 3, 6, or 10 mg/kg every month [6]. The second part of the trial was a phase II open-label study assessing two dosing regimens, 10 mg/kg every month versus 15 mg/kg every 3 months [6]. The primary endpoint was safety in the phase I dose-escalation study, immune monitoring in the phase I expansion cohort, and response in the phase II study [6]. Survival was analyzed as the secondary endpoint [6]. Among the 14 patients in the three dose cohorts, one patient in the 10-mg/kg dose group had a pathologically assessed PR of in-transit metastasis in the phase I study [6]. Table 2 presents the toxicities that were deemed possibly related to monthly dose administration of tremelimumab. In the phase I immune monitoring expansion study, three of 14 patients (all receiving tremelimumab at 10 mg/kg monthly) experienced an objective response, including in-transit and nodal metastasis [7]. The Kaplan–Meier estimate of median overall survival was 17.6 months for all dose groups combined (n = 28) (Table 3)[5].
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PHASE II CLINICAL EXPERIENCE
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Investigators conducted a two-stage, two-arm trial that was designed to select the optimal dosing regimen for pivotal clinical trial testing [8]. Eligible patients had measurable melanoma (stage IIIc or IV) progressing on or after prior therapy and an ECOG PS score of 1. In the first part of the study, 36 patients were randomized in a 1:1 ratio to receive tremelimumab at either 10 mg/kg monthly or 15 mg/kg every 3 months. If three or more patients in either arm had a CR or a PR, an additional 25 patients were added to that arm, which was the second stage of the trial. The primary endpoint of the trial was objective tumor response, and the secondary endpoints were safety and survival.
Eighty-nine patients received at least one dose, with 44 patients in the 10-mg/kg arm and 45 patients in the 15-mg/kg arm; both study arms moved to the second stage of the study [8]. Ninety-six percent of patients had stage IV disease, and 57% of patients had elevated lactic acid dehydrogenase (LDH). There were no significant differences in age, sex, stage, or baseline LDH level between the study arms. A median of three doses (range, 1–26) at 10 mg/kg and one dose (range, 1–9) at 15-mg/kg were administered. Dose delays occurred in 30% of patients in the 10-mg/kg arm and in 16% of those in the 15-mg/kg arm. At the time of publication, six patients in the 10-mg/kg arm had discontinued the study as a result of toxicity; of these, three had diarrhea/colitis (one requiring colectomy), Graves ophthalmopathy, pancreatitis, and hypersensitivity reaction. In the 15-mg/kg arm, there were two discontinuations: one patient reported colitis and pancreatitis and another patient reported diarrhea. No toxic deaths were reported in either group. Finally, the 15-mg/kg dose was associated with a lower incidence of grade 3 or 4 adverse events (13%, versus 27% for the 10-mg/kg group).
The best overall responses (Response Evaluation Criteria in Solid Tumors) by investigator assessment are presented in Table 4. Objective response rates (CR plus PR) were 10% (95% CI, 3%–23%) in the 10-mg/kg arm and 7% (95% CI, 1%–19%) in the 15-mg/kg arm [8]. Responses were noted in the skin, lymph nodes, bone, liver, lung, and adrenal glands. At the time of publication, only one patient in the 10-mg/kg group had relapsed after a minimum follow-up of 2 years, and the remaining responses were ongoing. The median survival times were comparable in the two treatment groups (10.3 months in the 10-mg/kg arm versus 11.0 months in the 15-mg/kg arm) and were not statistically different. The 15-mg/kg dose was selected for further clinical evaluation based on comparable antitumor efficacy and a trend toward better feasibility and safety compared with the 10-mg/kg dose [8]. Although the objective response rates were comparable in the two study arms, grade 3–4 toxicities attributed to study drug were twice as frequent among patients receiving the 10-mg/kg dosing regimen. The results of phase I/II testing (Table 3) support further study of tremelimumab at 15 mg/kg every 3 months as treatment for malignant melanoma in randomized clinical trials to test its effect on patient survival.
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BIOLOGIC AND IMMUNOMODULATORY STUDIES WITH TREMELIMUMAB
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A study conducted by Reuben and colleagues investigated the biologic and immunomodulatory effects of CTLA-4 blockade in patients with advanced malignant melanoma receiving tremelimumab and correlated effects with clinical responses [9]. The study included 30 patients who had participated in the phase I or phase II trials; 20 patients had received 10 mg/kg monthly and 10 had received 15 mg/kg every 3 months [9]. All patients underwent tumor assessment with magnetic resonance imaging of the brain and computed tomography of the chest, abdomen, and pelvis [9]. Peripheral blood was collected from each patient at study entry and at 14-day intervals afterward for lymphocyte immunophenotypes, including T-regulatory cells, by flow cytometry [9]. Therapy-related toxicities were recorded, and in this trial, immune-related adverse events (IRAEs) consisted of diarrhea and/or dermatitis of grade 2 or higher.
Analysis of the results suggested to the authors that antitumor response (ATR) is associated with the development of IRAEs (p = .0455) [9]. Among the 25 patients who did not attain an ATR, eight had IRAEs (IRAE+/ATR–), whereas 17 did not (IRAE–/ATR–). Among the five patients who did attain an ATR, three patients on the 10-mg/kg dose and one patient on the 15-mg/kg dose developed IRAEs (IRAE+/ATR+). Only one patient on the 15-mg/kg dose had an ATR with no IRAEs.
The authors of the study concluded that these results showed that CTLA-4 blockade therapy does succeed in breaking peripheral immune tolerance in some patients, but not in all [9]. Because these observations are based on a small sample size, larger trials are warranted to validate these predictions.
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ONGOING TRIALS WITH TREMELIMUMAB
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Other studies evaluating tremelimumab for the treatment of malignant melanoma are currently ongoing [10]. A phase II clinical trial of single-agent tremelimumab as second-line therapy in metastatic melanoma concluded enrollment in October 2006; the target enrollment was 215 patients. The primary endpoint of that trial is response rate. Patients with baseline serum LDH levels more than two times the upper limit of normal were excluded from participation.
A phase III trial concluded enrollment in July 2007; the target enrollment was 630 patients. That trial was designed to evaluate the overall survival of patients without prior therapy treated with single-agent tremelimumab versus dacarbazine (DTIC) or temozolomide. Inclusion criteria were surgically incurable melanoma, either stage IV or IIIc with N3 status for regional lymph nodes and in-transit or satellite lesions; LDH of two times the upper limit of normal or less; and an ECOG PS score of 0 or 1. Exclusion criteria were previous systemic therapy for metastatic melanoma, except postsurgical adjuvant treatment with cytokines (e.g., 
-interferon or GM-CSF) or with vaccines after complete resection or melanoma, and a history of brain metastases.
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CONCLUSIONS
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Clinical experience demonstrates that tremelimumab is a promising novel therapy for patients with malignant melanoma. Studies to date suggest that a subset of patients with metastatic melanoma derives long-term benefit from this agent. Serious inflammatory or autoimmune toxicities develop in some patients, which may require immunosuppressive therapy for adequate management, but administration of tremelimumab is safe in the majority of cases. Results of ongoing trials should define its role in the armamentarium of this disease.
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ACKNOWLEDGMENTS
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The primary author takes full responsibility for the content of this paper and would like to thank Wilma M. Guerra, ELS, for preparation of first draft, organization of the published literature, collation of author comments, and revision of the manuscript; Lisa Doelling for editing the manuscript; and Trudy Grenon Stoddert, ELS (Imedex) for preparation of the manuscript for submission. Medical writing and editing were supported by an educational grant from Bristol-Myers Squibb Company and Medarex, Inc.
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REFERENCES
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- Hanson DA, Canniff PC, Primiano MJ et al. Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206. Proc Amer Assoc Cancer Res 2004;45:877; Abstract 3802.
- Ribas A, Camacho LH, Lopez-Berestein G et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23:8968–8977.[Abstract/Free Full Text]
- Lee SY, Lee YH, Shin C et al. Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 2002;122:171–176.[CrossRef][Medline]
- Gomez-Navarro J, Antonia S, Sosman J et al. Survival of patients (pts) with metastatic melanoma with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study. J Clin Oncol 2007;25(suppl 18):8524.
- Ribas A, Bozon VA, Lopez-Berestein G et al. Phase 1 trial of monthly doses of the human anti-CTLA4 monoclonal antibody CP-675,206 in patients with advanced melanoma. J Clin Oncol 2005;23(suppl 16):7524.
- Ribas A, Comin-Anduix B, Bozon V et al. Antigen-specific T cell responses in patients with melanoma treated with the CTLA4 blocking mAb ticilimumab. J Clin Oncol 2006;24(suppl 18):8033.
- Ribas A, Antonia S, Sosman J et al. Results of a phase II trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma. J Clin Oncol 2007;25(suppl 18):3000.
- Reuben JM, Lee B-N, Li C et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer 2006;106:2437–2444.[CrossRef][Medline]
- U.S. National Library of Medicine. Phase 3 Trial of CP-675,206 Versus Either Dacarbazine or Temozolomide in Patients Without Prior Therapy. National Institutes of Health, Department of Health and Human Services. ClinicalTrials.gov. Available at http://clinicaltrials-nccs.nlm.nih.gov/ct/show/NCT00257205?order=4. Accessed August 24, 2007.
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Abstract
Introduction
