A Single-Arm Phase 2 Trial of Trametinib in Patients with Locally Advanced or Metastatic Epithelioid Hemangioendothelioma

Abstract

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE.

Patients and methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires.

Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib.

Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552.

Figure 1.

Kaplan-Meier Estimates of Progression-free and Overall Survival Kaplan-Meier estimates of progression-free survival (Panel A) and overall survival (Panel B). The cases in which TAZ-CAMTA1 translocation was detected by fusion-fluorescence in situ hybridization (fusion-FISH) in tumor tissue is shown in the blue line. Cases shown in orange had insufficient tumor tissue for fusion-FISH, the fusion-FISH test failed for technical reasons or the test did not detect chromosomal translocation involving TAZ and CAMTA1.

Figure 2.

Waterfall Plot of Tumor Response Percent change in the sum of the target lesion sizes as best response in the 24 patients with TAZ-CAMTA1 (Panel A) and the 11 patients without TAZ-CAMTA1 (Panel B) detected by fusion-fluorescence in situ hybridization (FISH) who had radiologic disease assessment at least once after starting therapy with trametinib. The patient denoted in grey was diagnosed with hemangioma on central review of pathology. The * denotes cases in which patients self-reported a reduction in pain after 4 weeks of trametinib.

Figure 3.

Time on and response to treatment Swimmers plot of time on treatment in months for the 27 patients with TAZ-CAMTA1 detected by fusion-FISH (Panel A) and the 15 patients without TAZ-CAMTA1 detected by fusion-FISH (Panel B). Seven patients did not have radiologic assessment of tumor response to treatment. Partial tumor response is indicated by red squares, stable disease by open circles, progressive disease by X. The patient with diagnosis of hemangioma on central pathology review is shown in yellow.