Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion

Abstract

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

<p>Malignant Gastrointestinal Neuroectodermal Tumors: Clinicopathological and Prognostic Features of 96 Patients</p>

“…Clinical management varied among the 8 patients who survived for more than 60 months. 16,17 Treatment with common antitumor drugs, such as ifosfamide, doxorubicin, crizotinib, and pazopanib, was noted. 18,19 Radiotherapy after lung and liver metastasis was also performed in some cases.…”

Intracranial myxoid mesenchymal neoplasms with EWSR1 gene rearrangement: report of 2 midline cases with one demonstrating durable response to MET inhibitor monotherapy

“… 13 There is also a report of using crizotinib to achieve long-term durable response in EWSR1-CREB1 fusion in a patient with gastrointestinal neuroectodermal tumor. 14 The presumed mechanism is that this fusion product results in upregulation of the MET pathway, sensitizing it to a receptor tyrosine kinase inhibitor such as crizotinib. Our goal for precision medicine treatment with crizotinib was 24 months but discontinued after 23 months because the patient had been experiencing fatigue, a known adverse effect with this drug.…”

Malignant Gastrointestinal Neuroectodermal Tumor (GNET) with Prolonged Disease-Free Survival after Platinum-Based Chemotherapy

“…Management options for clear cell sarcoma (CCS) and CCSLGT include surgical resection with regional lymph node dissection, radiotherapy, and chemotherapeutic regimens that include ifosfamide and doxorubicin [ 8 ]. Crizotinib and pazopanib were reported to offer a durable near complete response of about 1.5 years in one case report [ 8 ].…”