D’Amato, Gina Z.

In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964 ) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.

11507 Background: Advanced uterine leiomyosarcoma (uLMS) is an aggressive malignancy with poor prognosis. Standard-of-care treatments, including trabectedin (Tb) or pazopanib (P), provide median progression-free survival (PFS) of 3-4 months (mo) and objective response rates (ORR) of ~11%. Homologous recombination deficiency (HRD) in a subset of uLMS supports the use of PARP inhibitors combined with DNA-damaging agents. Preclinical studies demonstrated synergistic activity of olaparib and temozolomide (T+O), and a prior single-arm Phase II study of T+O showed promising efficacy independent of an established biomarker, warranting further investigation in a randomized setting. Methods: Alliance A092104 is a Phase II/III trial evaluating olaparib (200 mg BID) plus temozolomide (75 mg/m² daily, days 1-7, every 21 days) versus investigator’s choice of Tb or P in patients (pts) with advanced uLMS who progressed on ≥2 prior systemic therapies. Stratification factors included ECOG (0-1 vs. 2) and prior lines (2 vs. ≥3). The Phase II (Phase III) primary endpoint was PFS (OS), with a planned suspension of accrual at the end of Phase II. A total of 70 evaluable pts (58 PFS events) were needed to detect an improvement in PFS from 4 vs. 8 mo with power of 90% and 1-sided type I error of 10%, with futility assessed after 29 PFS events. Upon meeting the Phase II futility threshold for PFS, the trial was permanently closed. Data were released from the data and safety monitoring board. Pts continue to be followed for outcomes. Results: 74 pts enrolled (Arm 1: T+O, n = 37; Arm 2: investigator’s choice, n = 37 (Tb, 18; P, 13; 6 pts did not start treatment). The arms were balanced for baseline demographics except race, with the T+O arm having a higher proportion of black/African American (29.7% vs. 16.2%). 21 pts remain on treatment. Hematologic adverse events (AEs) were more frequent in the T+O arm, with Grade 4 neutropenia (19.5%) and thrombocytopenia (8.3%) both managed by dose reductions. Non-hematologic Grade 3 AEs were higher in the investigator’s choice arm (45.2% vs. 13.9%). No Grade 5 AEs were reported. In the first 70 pts, with a median follow-up of 5.9 mo, and 39 total PFS events, the median PFS was 3.2 mo (95% CI: 2.0-NE) for T+O versus 5.6 mo (95% CI: 2.8-NE) for investigator’s choice (HR = 1.00; 95% CI: 0.60-2.17; 1-sided stratified log rank p = 0.50). Within Arm 2, the median PFS for Tb and P were respectively 5.6 (95% CI: 3.1-NE) and 3.8 (95% CI: 1.5-NE) mo. 3 pts in the T+0 arm and 1 patient in the investigator’s choice arm (Tb) had a confirmed partial response. Conclusions: The trial did not meet its primary endpoint of PFS in Phase II. This suggests that a biomarker may be needed before there is further exploration of PARP inhibitor-based regimens in uLMS. Overall survival and analysis of tissue-based biomarkers will be presented. Clinical trial information: NCT05432791 .

Introduction This was the first phase 1 study conducted in the United States. It consisted of dose-escalation (part A) and multiple indication-specific cohort expansion (part B), investigating the safety and preliminary efficacy of toripalimab (anti–programmed cell death-1 inhibitor) in patients with advanced malignancies. Methods Patients with advanced malignancies that progressed after treatment with at least one prior line of standard systemic therapy, including the patients with advanced/recurrent cholangiocarcinoma (CCA), received toripalimab 240 mg every 3 weeks in part B. The primary endpoint was safety assessment. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (version 1.1) and overall survival (OS). Results In part B, 166 patients, including the 42 patients with CCA, were enrolled and received toripalimab. Among the 166 patients, treatment-emergent adverse events (TEAEs) of any grade occurred in 158 (95.2%) patients, and 97 (58.4%) patients experienced TEAEs of Grade 3 or greater. The most common TEAE was fatigue (42.2%). Seven (4.2%) patients experienced TEAEs with a fatal outcome, none of which were identified by investigators as related to toripalimab. Investigator-assessed immune-related adverse events (irAE) of Grade 3 or higher occurred in 7 (4.2%) patients. In the CCA cohort, with the median follow-up of 4.4 months, the ORR and DCR were 4.8% (95% CI: 0.58, 16.16) and 40.5% (95% CI: 25.63, 56.72), respectively; median DoR was 7.8 (range 4.4+ to 7.8) months; median PFS was 2.1 (95% CI: 1.91, 3.88) months; median OS was not estimable. Conclusions Toripalimab had manageable side effects in patients with refractory cholangiocarcinoma and exhibited preliminary evidence of anti-tumor activity. However, further information regarding biomarkers is needed. ClinicalTrials.gov ID: NCT03474640

11526 Background: There are no FDA-approved treatments for advanced cCS. Chemotherapy provides limited benefit. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type cCS harbor epigenetic dysregulation. In preclinical models, HDAC + DNMT inhibition (i) suppressed growth by inducing apoptosis, reversing the hypermethylated state, and upregulating expression of interferon (IFN) response genes including PDL1(1). This prompted a phase 2 study of HDACi + DNMTi in cCS, which failed to meet the 1° endpoint of ORR. The majority of pts had a best response of stable disease, with a trend towards improved mPFS in IDHm (2). Here we report correlative analysis of NCI 10330. Methods: NCI 10330 is a single-arm, multicenter, phase 2 study of belinostat with SGI-110 or ASTX727 in advanced cCS. All pts were required to have pre- and on-treatment (tx) biopsies (Cycle 2, Day 3-5). Tissue was evaluated with whole exome sequencing (WES) and RNA sequencing (RNAseq). From RNAseq, Tumor Inflammation Signature Scores (TISS) and Tumor Microenvironment functional Gene Set Enrichment Analysis scores (TME GSEA) were calculated as the mean of the log2 normalized counts of 18 signature genes (Danaher et al. J Imm Can 2018) and pre-defined gene sets (3), respectively. Wilcoxon rank sum test was used to analyze TME GSEA between pre- and on-tx samples. Differential expression was significant if |FC| > 1.33, adjusted P <0.01. Results: 19 pts were treated; all received paired biopsies. WES was adequate in 7/19 (37%) pts, with IDHm identified in 3/7 (43%) pts. All pts were MSI-stable, TMB: 1.01-3.57 mut/Mb. RNAseq was adequate in 7/19 (37%) pts at pre-tx and 5/19 (26%) pts at on-tx. TISS ranges trended higher for pre-tx (8.77-10.14) vs on-tx (7.36-9.51) samples. TME GSEA identified significantly enriched tumor immune infiltration (p < 0.05) in pre- vs on-tx samples. Differential analysis identified several gene sets related to inflammation overexpressed in pre-tx samples only, including IFN response. On-tx samples were enriched in myogenesis and coagulation gene sets. Conclusions: This is the first study to describe transcriptomic changes following epigenetic tx in cCS. Contradictory to our preclinical data, HDACi + DNTMi resulted in low expression of inflammation. Prior studies reported that the immune infiltrate of CS at progression is immunosuppressive; higher immune infiltrate is correlated with worse outcomes (4). Loss of inflammation may have implications for disease stability experienced by most pts on NCI 10330. Further analyses are planned to correlate TME (pro- vs anti-inflammatory infiltrates) and outcomes. Analyses are limited by small sample size, highlighting the challenges in collecting adequate CS specimens. 1. Sheikh, Schwartz et al. Mol Cancer Ther 2021. 2. Lacuna et al. ASCO 2023: #11531. 3. Bagaev et al. Can Cell 2021. 4. Richert et al. J Bone Onc 2020. Clinical trial information: NCT04340843 .

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 .

Abstract Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P &lt; 0.0001; exon 9, P = 0.0023; exon 13, P &lt; 0.0001; exon 17, P &lt; 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Abstract Background Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. Results Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7–6.4) and median PFS2 was 3.7 months (95% CI, 3.1–5.3). Median overall survival was 18.4 months (95% CI, 14.5–not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3–4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. Conclusion Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. Implications for Practice Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p <0.0001). In an earlier phase 1 dose escalation study, the maximum tolerated dose was not reached with doses up to 200 mg twice daily (BID). Here, we report efficacy, safety, and pharmacokinetic data for IPDE patients initially randomized to ripretinib from the phase 3 INVICTUS study based on data as of 10 Aug 2020. Methods: A total of 129 patients were randomized 2:1 to ripretinib 150 mg once daily (QD; n = 85) or placebo (n = 44). Patients receiving ripretinib 150 mg QD who had progressive disease (PD) as assessed by blinded independent central review (BICR) using mRECIST were given the option for IPDE to 150 mg BID. Tumor response assessments were performed every 28 days for 4 cycles and every 56 days thereafter (including after IPDE). The primary endpoint was PFS. For this exploratory analysis, PFS1 for IPDE patients was defined as the time from randomization to PD; PFS2 for IPDE patients was the time from the first dose of ripretinib 150 mg BID to PD or death. PFS1 and PFS2 were based on BICR. Results: Of 85 patients treated with ripretinib 150 mg QD, 43 patients with BICR PD dose escalated to 150 mg BID. Baseline characteristics of IPDE patients at time of study entry were similar to those observed in the original ripretinib QD arm and similar to the 22 patients with BICR PD who either remained on 150 mg QD or discontinued treatment. IPDE patients had a mPFS1 of 4.6 months (95% CI, 2.7–6.4) and a mPFS2 of 3.7 months (95% CI, 3.1–5.3); mPFS2/mPFS1=80%. The IPDE dosing period was well tolerated without the emergence of new safety concerns. The most common new or worsening (unchanged or improving grades not included) treatment-emergent adverse event (TEAE) for IPDE patients during the BID period was abdominal pain (30.2% all grades and 7% Grade 3–4 vs 41.9% and 4.7% in QD period, respectively). The most common Grade 3–4 TEAE in the BID period was anemia (14% vs 2.3% in QD period). IPDE from QD to BID resulted in an approximately 2-fold increase in the steady state trough concentration. Conclusions: Similar to the phase 1 study wherein IPDE to 150 mg BID following PD provided clinical benefit with a mPFS1 of 5.5 months and mPFS2 of 4.6 months (mPFS2/mPFS1=84%) for patients with ≥4th-line GIST, these analyses from INVICTUS indicate that IPDE to ripretinib 150 mg BID can also provide additional meaningful clinical benefit and a similar tolerability profile to the 150 mg QD regimen for patients with ≥4th-line GIST that progressed following treatment with ripretinib 150 mg QD. Clinical trial information: NCT03353753.

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .