Gina D'Amato

Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

PURPOSE Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. PATIENTS AND METHODS Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. RESULTS A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. CONCLUSION Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

Update on the biology and therapy of gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are an example of a disease with an effective, molecularly targeted therapy. METHODS Published articles and author experience were used to comprehensively define the clinical features, biology, and state-of-the-art therapy of GISTs. RESULTS GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal, the intestinal pacemaker cells. GISTs commonly have mutations in the kit gene, resulting in a gain-of-function mutation and ligand-independent constitutive activation of the KIT receptor tyrosine kinase. Successful tyrosine kinase inhibitors target the aberrant pathways that are critical for tumor cell viability. The development of imatinib mesylate (formerly STI 571) in the treatment of metastatic GISTs represents a therapeutic breakthrough. CONCLUSIONS Progress in the clinical diagnosis has led to an increased recognition of this disease as a distinct clinical entity. Treatment of metastatic GIST with imatinib has led to unprecedented improvements in progression-free and overall survival. The use of imatinib in the preoperative and postoperative treatment of GISTs is an area of intense investigation.

Sunitinib Treatment in Pediatric Patients With Advanced GIST Following Failure of Imatinib

Sunitinib inhibits KIT and other members of the split‐kinase‐domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib‐resistant gastrointestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib.

Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma

Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate‐refractory gastrointestinal stromal tumors). This single‐institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty‐eight patients were enrolled, and 35% were heavily pretreated (≥2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression‐free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1 and 2.5 and 13.6 months, respectively. The 3‐month progression‐free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma and MFH were 75% and 69.2%, 60%, and 62.5% and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low‐grade disease could have been included and the small numbers, a 3‐month progression‐free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.

Therapeutic potential of directed tyrosine kinase inhibitor therapy in sarcomas.

BACKGROUND Sarcomas are rare mesenchymally derived tumors for which there are limited treatment options. This paper discusses the current therapeutic potential of directed tyrosine kinase inhibitors (TKIs) in sarcoma. METHODS The authors review antibody-based strategies and small molecular inhibitors of TKIs, with specific emphasis placed on the potential use of these targeted agents as therapeutic options for the treatment of sarcomas that are not gastrointestinal stromal tumors. RESULTS Many TKs have been shown to be mutated or overexpressed in human sarcoma tumors and cell lines and may serve as potential targets for promising new sarcoma therapies. Furthermore, the novel mechanism of targeting TKs may complement the antitumor activity of existing sarcoma treatment options. CONCLUSIONS TKIs such as imatinib, sunitinib, and sorefanib are promising new therapeutic options for the management of patients with soft tissue sarcoma.

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor

Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed.

Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib

Importance Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor &agr; (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.