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New Biological Agents for the Treatment of Cervical Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Pazopanib, an orally administered tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), demonstrated superior clinical efficacy to lapatinib, a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2/neu), in women with advanced stage or recurrent cervical cancer. A planned futility analysis deemed the combination was unlikely to be superior to single agent pazopanib.
Source: Monk BJ, et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazo-panib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol 2010;28:3562-3569.
Previous investigation of cervical cancer biology has revealed a dependence on VEGF, among other factors, for growth and metastases. This dependence is mediated by HPV infection and by ubiquitous hypoxia, which is also recognized as a poor prognostic factor. It also has been demonstrated that cellular growth signaling through the ErbB receptors is prevalent in cervical cancer. These observations underscore the study's rationale and hypotheses.
Pazopanib, an oral TKI targeting VEGFR, cKit, and platelet-derived growth factor receptor (PDGFR), and lapatinib, an oral TKI targeting EGFR and HER2/neu, were used in this three-arm study as monotherapy or in combination. All patients were required to have measurable disease and to have been treated at least once with systemic chemotherapy. Of the 230 enrolled patients, 152 were randomly assigned to one of the monotherapy arms. Overall, approximately 70% had squamous cell histology and 62% had recurrent disease. A planned interim futility analysis assessed the performance of the combination arm against lapatinib monotherapy. This analysis demonstrated increased toxicity and a low likelihood that the combination would exceed efficacy of lapatinib, resulting in discontinuation of the combination therapy arm. Relative to lapatinib, pazopanib increased progression-free survival (hazard rate [HR], 0.66; P = 0.013) and overall survival (OS; HR, 0.67; P = 0.045). Median OS for pazopanib or lapatinib was 51 weeks vs 39 weeks, and response rates were 9% and 5%, respectively. Grade 3 and 4 toxicities were infrequent with either compound (diarrhea: 11% pazopanib, 13% lapatinib). The authors conclude that anti-angiogenesis targeting is a viable approach in women with advanced and recurrent cervical cancer, with pazopanib being a well-tolerated and active agent worthy of further investigation.
Patients with advanced stage cervical cancer not amenable to curative therapy and those with recurrent disease have few therapeutic options. While most will receive systemic chemotherapy, the majority ultimately will progress on treatment or within a short duration of completing treatment. Since many of these patients will receive our most active agents in first recurrence, the options upon progression are extremely limited and define a clear unmet medical need. Unfortunately, the rarity of the disease in the United States and the difficulty of clearing an efficacy benchmark generally has tempered enthusiasm for drug development. Nevertheless, there are clear "druggable" targets, upon which modulation appears to hold some promise for subsequent clinical development.
Bevacizumab, a monoclonal antibody to VEGF, has also been evaluated in this setting and demonstrated similar efficacy to pazopanib. Those promising results prompted the development of an ongoing randomized phase III study addressing the utility of adding bevacizumab to one of two chemotherapy backbones in women with advanced or recurrent cervical cancer who have not received previous systemic chemotherapy (GOG 240). However, what is striking in this report is the continued apparent disconnect between EGFR targeting and efficacy. The experience with lapatinib joins several EGFR-targeted agents assessed in this disease, each with disappointing results. Most squamous cell cervical cancers overexpress this target, and its presence is a poor prognostic factor.
However, whether administered alone or in combination with chemotherapy, EGFR-targeted monoclonal antibodies and small molecule inhibitors have produced limited signs of efficacy. In the current trial, EGFR or HER2/neu overexpression was not an eligibility requirement, and tissue was not procured for assessment of expression, gain-of-function mutations, or the presence of ras/raf activation. Based on results with other solid tumors, such information could have brought clarity to the clinical observations and should be the focus of future work in this disease.