(P 111) INTERNATIONAL MULTICENTER RETROSPECTIVE STUDY OF SPINDLE CELL/ SCLEROSING RHABDOMYOSARCOMA (S-RMS), A PUSH PLATFORM STUDY: OUTCOME OF LOCALIZED AND ADVANCED DISEASE

Objective: Spindle cell/sclerosing rhabdomyosarcoma (S-RMS) is an ultra-rare sarcoma with a 5-year overall survival (OS) ranging between 30% and 75%, though our understanding of this disease is limited due to its rarity. S-RMS has histopathologic and genomic features distinct from alveolar or embryonal RMS. We report on a series of patients (pts) with primary localised and metastatic S-RMS collected within the PUSH platform, a global consortium aimed at improving knowledge of and developing new treatments for ultra-rare sarcomas.

Methods: This is an international, multicentre, retrospective study conducted within the PUSH platform of all pts of any age affected by primary localized, locally advanced and/or metastatic S-RMS at the participating institutions (30 sites) from January 2013 to December 2023. Data retrieved included loco-regional and/or systemic therapies. Eligible pts had a pathologically confirmed diagnosis of S-RMS (requiring desmin and variable either Myf4 or MYOD1 expression and one of the following genetic alterations: VGLL2/NCOA2/CITED2/TEAD1/SRF rearrangements; MYOD1 p.Leu122Arg; EWSR1 or FUS::TFCP2; MEIS1::NCOA2), as defined by the sarcoma experts pathologist of the project committee. Central review of the genetic alterations is available. Main endpoints included OS, disease-free survival (DFS) and progression-free survival (PFS). Data collection is still ongoing, and final data lock is planned in August 2024. Results will be updated (cases expected from 19/30 remaining sites).

Results: As of May 31, 2024, 37 cases (11 pending central molecular confirmation) from 11/30 institutions were identified; 25 and 20 were included in the localized (Table 1) and metastatic/ locally advanced (Table 2) disease subgroup analysis, respectively.

Localized disease
At a m-FU of 36.4 (IRQ: 19.64, 80.13) mos, 4/25 (16%) patients died and 20/25 (80%) had local recurrence (LR) or distant metastasis (DM). m-OS was not reached (NR) (CI: 58.4-NR); 3-year OS was 93.3% (CI: 81.5-100), m-DFS was 23.8 (CI: 18.0-NR) mos and 3-year DFS was 43.1% (CI: 26.5- 69.9). LR developed in 12/25 (48%) pts (median time to LR 10.4 mos) and the 3-year crude cumulative incidence (CCI)-LR was 48% (CI: 26-67). DM developed in 8/25 (32%) pts (median time to DM 18.7 mos) and the 3-year CCI-DM was 28% (CI:11-48). Surprisingly, no patient had concomitant LR and DM relapse. For the localized S-RMS patients, the most common prescribed chemotherapy was anthracycline-based regimen (n = 10) and receiving chemotherapy is associated with significantly lower risk of LR (HR 0.23, 95% CI 0.07-0.74, p = 0.014) but not DM (p = 0.55). Every increase in 1 mm in primary tumor size is associated with a 1% increase in DM risk (p < 0.001).

Metastatic/ locally advanced disease
At a m-FU of 17.9 (IRQ: 14.1, NR) mos, 12/17 (70.5%) died and the median OS was 14.8 (CI: 10.1-NR) mos. The median PFS of first-line treatment was 10.9 (CI: 7.0-NR) mos. 14/17 (82%) patients received systemic chemotherapy as first-line therapy (11 anthracycline-based, 2 gemcitabine-based, and 1 ifosfamide based). Among 15 best response evaluations of first-line treatment, 5 (33.3%) were PR, of which 4 (80%) were patients with EWSR1 rearrangement. Those received anthracycline-based regimens (inclusive of all lines) had a median PFS of 6.3 (CI: 2.6-NR) mos, and a median OS of 16.7 (CI: 11.3-NR) mos, calculated from the date treatment started. The details of efficacy results including other regimens (i.e., gemcitabine-based, irinotecan-based, pazopanib, and other) will be reported at the conference.

Conclusion: The PUSH platform successfully collected S-RMS cases from global investigators with its genomic features identified. These preliminary results, to be confirmed in the larger series that will be available at the meeting, showed that 80% of localized S-RMS developed recurrence with a higher likelihood for local failure. In the metastatic/ locally advanced setting, the pattern of systemic treatment showed that anthracycline-based regimen, rather than the RMS VAC regimen, was more commonly administered. The genomic feature of S-RMS may be associated with tumor response to systemic treatment(s).