Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study

Abstract

Purpose

The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix.

Patients and methods

Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤ 2. Treatment consisted of cetuximab 400 mg/m² initial dose followed by 250 mg/m² weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design.

Results

Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n = 25, 71.4%) or 2 (n = 10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n = 5), GI (n = 4), anemia (n = 2), constitutional (n = 3), infection (n = 2), vascular (n = 2), pain (n = 2), and pulmonary, neurological, vomiting and metabolic (n = 1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology.

Conclusion

Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.

Introduction

Cervical cancer remains the second leading cause of cancer death among women worldwide and remains an important health problem for women especially in underserved and minority groups in the Unites States [1]. Although cervical cancer can be cured by radical surgery or radiotherapy with equal effectiveness, pelvic chemo-radiation represents the standard therapy for the treatment of locally advanced disease [2]. Despite technological advances, however, up to 35% of patients overall will develop persistent/recurrent/metastatic disease. Platinum-based chemotherapy represents the gold standard therapy for the treatment of cervical cancer patients who have not responded to primary therapy or have recurrent disease no longer amenable to control with surgery and/or radiation therapy. Unfortunately, most responses to chemotherapy are partial and of short duration, and the most effective treatment of patients with progressive disease on platinum-based chemotherapy has yet to be defined.

The epidermal growth factor receptor (EGFR; HER1/erbB-1) has recently been identified as a target for cancer therapy in multiple human tumors [3], [4], [5], [6], [7], [8]. On endogenous ligand binding, EGFR activation occurs, with receptor homo- or heterodimerization and autophosphorylation of the intracellular tyrosine kinase domain [9], [10]. Subsequently, a complex network of signal transduction pathways is induced, which plays a key role in regulating cell proliferation, differentiation, motility, invasion, and angiogenesis [9], [10], [11], [12], [13]. EGFR is expressed in a variety of human malignancies and its high level of expression has been previously correlated with poor patient prognosis and resistance to treatment in many tumor entities including cervical carcinoma [13], [14], [15], [16], [17], [18].

Cetuximab (C225) is a human/murine chimeric monoclonal antibody formed by cloning the heavy and light chains of the murine antibody (M225) and adapting them for expression with the constant regions of the human immunoglobulin kappa light chain and gamma 1 heavy chain [4], [6], [19]. Preclinical studies have demonstrated that cetuximab binds to the EGFR with high affinity and is able to compete with EGF and TGFα binding, thereby inhibiting subsequent receptor activation and signaling [20], [21]. In addition, binding of cetuximab to EGFR induces receptor dimerization, internalization and receptor down regulation [22], [23]. These processes may consequently lead to several effects such as cell-cycle arrest via upregulation of cyclin-dependent kinase inhibitor p27^KIP1, and potentiation of apoptosis [24], [25]. Other effects include inhibition of tumor production of VEGF leading to reduced tumor microvessel density and inhibition of invasion and metastases by inhibiting matrix metalloproteinases [26], [27].

Clinical studies of cetuximab either alone or in combination with cytotoxic agents have demonstrated efficacy in patients with chemotherapy-refractory head and neck or colorectal cancer [28], [29], [30], [31], [32]. In patients with irinotecan-refractory advanced colorectal cancer, treatment with cetuximab either as a single agent or in combination with irinotecan resulted in overall remission rates of 10.8% (95% CI, 5.7% to 18.1%) and 22.9% (95% CI, 17.5% to 29.1%), respectively [30], [31]. Similar results have been reported for patients with platinum-refractory head and neck cancer or non-small-cell lung cancer with cetuximab in combination with chemotherapy [32].

Cervical cancer patients with metastatic/recurrent disease not amenable to radical local excision or regional radiation and who have progressed on platinum-based chemotherapy have limited therapeutic options. The GOG conducted a phase II trial of single-agent cetuximab in patients with persistent or recurrent squamous or non-squamous cervical carcinoma. The primary endpoints of this study were the frequency of patients with tumor responses or who survived progression-free for at least 6 months (PFS at 6 months). The secondary objectives were to estimate the distribution of overall survival (OS), the distribution of PFS, the duration of objective response, and the frequency and severity of adverse events.