(P 429) PATIENTS WITH ADVANCED EPITHELIOID HEMANGIOENDOTHELIOMA TREATED WITH SIROLIMUS: OUTCOME FOLLOWING SIROLIMUS DISCONTINUATION.

Objective: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma with poor sensitivity to conventional chemotherapy commonly used for sarcomas. Sirolimus is a systemic treatment for advanced and progressive EHE. The largest series of sirolimus-treated EHE cases, reported by the Italian Rare Cancer Network (Stacchiotti et al., Cancer 2021), showed a median progression-free survival (m-PFS) of 13 months and a median overall survival (m-OS) of 18.8 months. To better understand sirolimus's role in EHE, which can exhibit indolent behavior in some patients, we reviewed outcomes of patients with advanced EHE who discontinued sirolimus.

Methods: We considered all consecutive pts with a molecularly confirmed diagnosis of EHE who received sirolimus from January 1, 2010 to June 2024, 1 (data cut-off). This includes patients from the published retrospective series treated within IRCN centers and those enrolled in the ongoing prospective observational study at the National Cancer Institute (Milan), and the Royal Marsden (London). The analysis focused specifically on pts who discontinued sirolimus for any reason and for >/= 2 months (shorter discontinuation were not included). The outcome of pts who re-challenged sirolimus was also evaluated. Progression was categorized by RECIST 1.1 (PD), and as “clinical progression” (CP), the latter defined as worsening of tumor-related systemic symptoms and serosal effusion without the criteria for RECIST PD. Survival analyses were performed by Kaplan-Meier method. Post-discontinuation OS (pOS) was defined as the time from sirolimus discontinuation until death or last FU, post-discontinuation PFS (pPFS) as the time from sirolimus discontinuation until first evidence of progression (PD or CP) or death, post-rechallenge OS (pR-OS) as the time from sirolimus re-challenge until death or last FU, post-rechallenge PFS (pR-PFS) as the time from sirolimus re-challenge until first evidence of progression (PD or CP) or death.

Results: Thirty-one pts who discontinued sirolimus for >/= 2 months (24 from the retrospective series, 7 from the prospective observational study) were identified (median age = 47 years; serosal effusion yes/no = 11/20). Table 1 shows the main patient characteristics. Reasons for sirolimus discontinuation were: progression = 18/31 (RECIST PD = 13, CP = 5), toxicity = 8/31; other = 5/31.

At a m-FU of 81.3-mos (IQR: 46.1-143.1), 8/31 (26%) pts were alive with disease, 23/31 (74%) dead. 23/31 (74%) pts did not receive any further systemic treatment, while 12/31 (35%) progressed and started again a systemic therapy, 6/12 sirolimus, 6/12 other (2 gemcitabine, 1 interferon, 1 paclitaxel, 1 pazopanib, 1 trametinib).
The overall (31 pts) m-pPFS (Fig.1A) was 3.0 mos (95% CI, 1.9-4.0), while the m-pOS was 7.2 mos (95% CI, 2.9-11.4).
Of the 13/31 (42%) pts who discontinued sirolimus without evidence of progression, 9/13 progressed (6 RECIST PD, 3 CP), 2/13 died of disease and 2/13 remained progression-free. In these pts, m-pPFS (Fig.1B) was 3.02 mos (95% CI, 2.2-3.8), and m-pOS was unreached. While in the 18/31 (58%) pts who discontinued sirolimus with evidence of progression, m-pPFS (Fig.1C) was 2.5 mos (95% CI, 0.7-4.2), and m-pOS was 2.9 mos (95% CI, 0.0-8.2).

Of the 6 pts who restarted sirolimus, 1/6 pt died of disease after 37 mos from sirolimus re-challenge, while 5/6 pts were alive; the best response was RECIST stable disease in 5/6 pts, RECIST PD in 1/6 pt. In these pts, at a 81.3-mo m-FU (IQR: 62.2-143.1), m-pR-PFS (Fig.1D) and m-pR-OS were unreached.

Conclusion: This retrospective study showed a poor outcome for pts with advanced EHE after the discontinuation of sirolimus. In addition, with the limit of small patient numbers, this study indicates that a subset of advanced EHE pts derive durable clinical benefit from sirolimus rechallenge. This provides further evidence of the antitumor effect of sirolimus in EHE.