Systemic Therapies for Locally Recurrent or Metastatic Disease

Imatinib

Imatinib mesylate is a tyrosine kinase inhibitor that targets c-KIT, PDGFR-A and B, and BCR-ABL. Imatinib’s first success in a solid tumor was in another connective tissue malignancy, gastrointestinal stromal tumor (GIST). Prompted by the tumor tissue expression and activation of PDGFR-B in chordoma and a lack of other standard options, Casali et al. treated six patients with advanced chordoma using imatinib at a dose of 800 mg daily. Although there were no objective responses based on RECIST, they noted changes in chordoma characteristics on imaging (liquefaction, decreased contrast enhancement and decreased glucose uptake) consistent with tumor response to treatment. Patients also reported decrease in tumor-related symptoms, predominately pain, while undergoing treatment. This study suggested that although patients derived benefit from imatinib, response was not quantifiable by standard criteria, a finding similar to that in patients with GIST treated with imatinib, which prompted development of the Choi criteria.

Studies by Tamborini and colleagues expanded upon the initial investigation of PDGFR-B in chordoma by evaluating PDGFR-A, PDGFR-B, and c-KIT protein expression in 31 chordoma tumors by immunoprecipitation, Western blot analysis and immunohistochemistry. PDGFR-B was found to be highly expressed and phosphorylated. PDGFR-A and c-KIT were also activated but were expressed at much lower levels. No activating or point mutations were identified in the tyrosine kinase receptors, supporting the concept of activation through autocrine/paracrine secretion of receptor ligand. This work led to further investigation of imatinib in patients with advanced PDGF-B and/or PDGFR-B-positive chordomas. The primary endpoint for the phase II nonrandomized study of was overall response rate (ORR) by RECIST. Patients were treated with imatinib 400 mg twice daily. Only one partial response was observed in 51 evaluable patients. A reduction in tumor uptake of FDG assessed by positron emission tomography (PET) was seen in 39% of patients at 3 months, suggesting that traditional RECIST criteria may not be the optimal considerations for detecting tumor response to small molecule inhibitors of receptor kinases. Tumor-related pain, assessed by a patient-reported pain inventory survey, improved during treatment with imatinib. The median duration of PFS was 9.2 months, and median overall survival (OS) was 34 months. While the median PFS seems clinically favorable compared to other reports of metastatic chordoma patients, the indolent nature of the disease and the lack of documented tumor progression prior to enrollment in the study may have significantly influenced the results. The true benefit of imatinib in this patient population is challenging to discern in the setting of single-arm, nonrandomized, clinical trials in which PFS or OS are primary study end-points. A follow-up retrospective analysis of 48 patients with PDGF-B/PDGFR-B positive advanced chordoma treated with imatinib 800 mg per day echoed the results of the aforementioned study. Of 46 patients evaluable for response, the best response was stable disease in 34 patients (74%) and progressive disease in 12 patients (26%). Seventy percent of the patients required reduction in dose of imatinib (600 mg per day in 19 patients and 400 mg per day in 14 patients) because of adverse drug effects. The median PFS was 9.9 months, and the median OS was 30 months. These findings add to the growing data that imatinib may help stabilize disease growth in locally advanced and metastatic chordoma but does not result in significant regression of tumor.