1.
Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein.
Subbiah, V, Westin, SN, Wang, K, Araujo, D, Wang, WL, Miller, VA, Ross, JS, Stephens, PJ, Palmer, GA, Ali, SM
Journal of hematology & oncology. 2014;:8
Abstract
BACKGROUND Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial. METHODS Genomic profiling with clinical next generation sequencing was performed on the FoundationOneā¢ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199). RESULTS The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial. CONCLUSIONS The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.
2.
Rationale and protocol of SOAP: a phase II study to evaluate the efficacy of sorafenib as second-line treatment after pazopanib in patients with advanced renal cell carcinoma.
Iacovelli, R, Verzoni, E, Grassi, P, Farcomeni, A, de Braud, F, Procopio, G
Tumori. 2014;(6):e282-5
Abstract
The introduction of agents targeting vascular endothelial grow factors has radically changed the approach to metastatic renal cell carcinoma; however, cure is not within definitive reach. In many cases, the tumor will progress several months after the start of first-line therapy and new lines of therapy are required. Pazopanib and sorafenib are two frequently used targeted agents, and no sound data are currently available for patients who relapsed after pazopanib. In this paper we illustrate the SOAP study, which was designed to evaluate the safety and efficacy of sorafenib in terms of progression free-survival in 44 patients treated in 10 Italian centers who had relapsed after first-line pazopanib. Standard treatment with sorafenib will be administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety and quality of life. A subanalysis to evaluate toxicities as predictive factors has also been planned.
3.
Clinical efficacy of targeted biologic agents as second-line therapy of advanced thyroid cancer.
Owonikoko, TK, Chowdry, RP, Chen, Z, Kim, S, Saba, NF, Shin, DM, Khuri, FR
The oncologist. 2013;(12):1262-9
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Abstract
UNLABELLED Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established. METHODS We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant. RESULTS We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6-8.2), and median PFS (4.6 months; 95% confidence interval: 3.2-8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months). CONCLUSION Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.