Bose, Sminu

PURPOSE Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

11531 Background: Conventional chondrosarcoma (cCS) is the 2nd most common primary bone tumor and is resistant to chemotherapy and radiation. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type (wt) cCS harbor epigenetic dysregulation. In preclinical models of IDHm and wt cCS, combination treatment with HDAC and DNMT inhibitors (i) suppressed growth in vitro and in vivo by reversing the hypermethylated state and inducing tumor suppressors, interferon response genes and apoptosis (Sheikh T, Schwartz G. Mol Cancer Ther 2021;20). Methods: NCI 10330 is a single-arm, multicenter, phase 2 study evaluating the HDACi belinostat (B) with the DNMTi SGI-110 (S) or ASTX727 (A). A replaced S due to drug availability (pts were replaced). Pts had advanced cCS, ECOG PS ≤ 2 and could be treatment naïve. Progression was required for grade 1 cCS. Pts received B 1000mg/m2 IV + S 45mg/m2 SC both days 1-5 or B (same dosing) + A (cedazuridine 100mg/decitabine 35mg) PO both days 1-5, in 28-day cycles. 1° endpoint was objective response. A Simon 2-stage design was used. If ≥ 2/13 responses occurred in stage 1, the study would proceed to full accrual. Design had 85% power with α = 0.05 to test ORR 8% vs 28%. 2° endpoints included safety, PFS and OS. A safety lead-in was performed. Paired biopsies were collected. Results: Stage 1 is complete. 19 pts were treated: 6 on B+S and 13 on B+A. Median age was 50 and 67 years, respectively. All pts had prior surgery. 17% (B+S) and 38% (B+A) had prior radiation. 33% (B+S) and 55% (B+A) were IDHm. 67% (B+S) and 75% (B+A) were histologic grade ≥ 2. There were no objective responses. Best response (at 8 weeks) was stable disease (SD) in 4/6 pts (67%) on B+S and 6/10 pts (60%) on B+A. mPFS was 4.2 mos (95% CI 1.97-NR) for B+S and 3.8 mos (95% CI 2.17-NR) for B+A. mOS has not been reached. For B+A, mPFS for IDHm vs wt pts was 4.7 and 3.1 mos, respectively (p=0.21). One pt with IDHm grade 2 cCS who progressed on FT-2102 (IDH1i) remains on B+A > 1 year. There were no DLTs during either safety lead-in. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17% (B+S) and 69% (B+A). For B+A, the most common grade 3/4 TRAE was neutropenia (54%) and the most common all-grade TRAEs were nausea (69%), leukopenia (61%), neutropenia (54%), anemia (46%) and fatigue (46%). Paired tumor biopsies are being evaluated with whole exome sequencing, RNAseq, methylation array and multiplex IHC with results forthcoming. Conclusions: Combination HDACi + DNMTi was well-tolerated in advanced cCS. There were no objective responses; however, a subset of pts experienced prolonged SD with a trend towards improved mPFS in IDHm pts. Correlative work is ongoing with a focus on differential effects on IDHm tumors and whether modulation of the immune microenvironment might support combinations with immunotherapy. Support: UM1CA186689. Clinical trial information: NCT04340843 .

11509 Background: uLMS is an aggressive sarcoma subtype of smooth muscle origin. Chemotherapy provides limited benefit for advanced disease. 18-25% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. uLMS exhibits high levels of replicative stress. These findings prompted a phase 2 study of O+T in pretreated uLMS where O+T demonstrated activity: ORR 27%, mPFS 6.9 mos (Ingham M. et. al. ASCO 2021: #11506) Methods: NCI protocol #10250 is a single-arm, multicenter, phase 2 trial evaluating O+T in advanced uLMS pts with progression on ≥1 prior line. Pre-treatment (Pre) and on-treatment (On) biopsies were collected from 22 pts. In prespecified analysis, we evaluated for a relationship between clinical outcomes and HR gene alterations by whole exome sequencing (WES), SLFN11/MGMT expression by RNAseq, and RAD51 foci formation (functional assay). HRD scores were calculated from WES using scarHRD. Gene expression was evaluated using a Spearman rank-order correlation analysis to identify genes associated with PFS (p < 0.01) and overexpressed in sensitive (S: PFS > 240d) or resistant (R: PFS < 240d) pts. Gene set enrichment analysis (GSEA) was performed (q = FDR-adjusted p value). Pts with available results: WES/RNAseq (16), Pre HRD score (13), Pre RAD51 foci (12). Results: 31% (5/16) pts had a mutation (Mut) or homozygous deletion (Hd) in the HR panel: ATRX Mut (2), ATR Mut, PALB2 Hd, RAD51B Hd. Pts with PALB2 and RAD51B Hd had longest PFS on study. Recurrent alterations also occurred in TP53 (56%) and RB1 (19%). Median HRD score in Pre samples was 51 (range 36-66) and 10/13 had HRD scores ≥ 42. Pre and On SLFN11 and MGMT RNA expression were not correlated with ORR/PFS. 6/13 Pre samples were HR-deficient by the RAD51 foci assay. Of pts with PFS ≥ 200d, 4/6 were HR-deficient. In Pre samples, 81 genes were overexpressed in S pts and 73 in R pts. In On samples, 146 genes were overexpressed in S pts and 127 in R pts. In On samples, GSEA identified the epithelial-mesenchymal transition enriched in S pts (q = 3.38e-7) and cell cycle pathways (E2F targets, G2M checkpoint) in R pts (q = 7.43e-4). Only 2 genes, CXCL10 and PCDH15, were differentially expressed between paired Pre and On samples (both increased in On). Gene expression signatures for replicative stress showed borderline association with worse PFS. Conclusions: Most uLMS tumors exhibit HR defects as measured by HRD scores. A subset of pts with greater benefit from O+T were identified by WES for HR genes and the RAD51 assay. There was no correlation between SLFN11 and MGMT expression and outcomes. GSEA identified pathways differentially expressed in S and R pts in On samples. O+T induced CXCL10 which has been associated with T-cell trafficking to tumors. A randomized phase 3 trial of O+T versus investigator’s choice is planned. These results provide insight into which pts may benefit most from this novel drug combination. Clinical trial information: NCT03880019.