Wagner, Andrew J.

LBA2 Background: Dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat with limited systemic therapy options. Approved drugs offer modest benefit such as trabectedin (median progression-free survival [mPFS] 2.2 months [m]) or eribulin (mPFS 2.0m). The Cyclin-dependent kinase 4 (CDK4) oncogene is ubiquitously amplified in DDLS and is a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in mPFS 4.2m with palbociclib and mPFS 7.7m with abemaciclib. We hypothesized that treatment with abemaciclib would improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: SARC041 was a phase 3 randomized double-blind study of abemaciclib versus placebo. The study was open at 9 academic medical centers in the USA. Eligible patients (pts) had recurrent or metastatic DDLS (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Pts were stratified by prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day or matching placebo. Scans were every 6 weeks (every 12 weeks after week 36) and pts with progression of disease on placebo could cross over to open label abemaciclib. The primary endpoint was PFS. The design provided 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6 by log-rank test. Secondary endpoints were overall response rate (ORR), PFS and response rate after crossover, and overall survival (OS). Data cutoff was March 1, 2026. Results: In total, 108 pts were randomized to receive abemaciclib (n = 54) or placebo (n = 54). Demographic/baseline characteristics were generally similar across treatment arms. Abemaciclib demonstrated a statistically significant improvement in PFS at 9.67m vs placebo at 1.52m (hazard ratio [HR] 0.39; 95% confidence interval [CI], 0.25–0.59; p < 0.001). ORR was 9.3% for abemaciclib vs 0% for placebo (p = 0.057). mOS was not reached with abemaciclib vs 25.45m with placebo (HR 0.55; 95% CI, 0.28–1.07; p = 0.077). mPFS after crossover from placebo to abemaciclib was 3.44m (95% CI 2.66, 6.84). ORR after crossover was 4.3% (95% CI 0.53%, 15%). mOS after crossover was 24.03m (95% CI: 11.7, NA). Grade 3 or higher adverse event rates were similar in both arms (p > 0.99). No new safety signals were observed. Conclusions: Abemaciclib demonstrated a statistically significant improvement in PFS vs placebo in pts with dedifferentiated liposarcoma, with an encouraging OS trend. These results support abemaciclib as a new treatment option for dedifferentiated liposarcoma. Clinical trial information: NCT04967521 .

TPS11579 Background: Gastrointestinal stromal tumors (GIST) are commonly driven by mutations in the receptor tyrosine kinase KIT . Resistance to approved tyrosine kinase inhibitors (TKIs) arises from additional KIT mutations in the ATP-binding pocket (AP) and activation loop (AL). No single approved TKI broadly suppresses all resistant clones, and overlapping VEGFR inhibition and toxicity limits TKI combinations. The type I TKI bezuclastinib (“BEZ,” CGT9486) inhibits KIT AL resistance mutations, does not inhibit VEGFR, and has complimentary activity with sunitinib (“SUN,” inhibitor of KIT AP resistance mutations). The first-in-human study (PLX121-01) and ongoing Peak trial (NCT05208047) evaluated BEZ+SUN showing promising safety and efficacy in GIST. SARC044 investigates BEZ+SUN in patients (pts) with SUN-resistant, KIT-mutant GIST, and correlatives aim to determine mechanisms of response and resistance (NCT06208748). Methods: SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult pts with KIT exon 9 or 11-mutant GIST resistant to imatinib and SUN. After TKI washout (baseline, “b/l”), pts initiate BEZ 600 mg daily for 2 weeks, then add SUN 37.5 mg daily, taking both drugs continuously (28-day cycles) until mRECISTv1.1 progression or unmanageable toxicity. Response evaluations (RE) are performed every 8 weeks (wk) through 15 months (mo) on study, then every 12 wk. Circulating tumor DNA (ctDNA) is collected at b/l, cycle 1 day 15 (C1D15), C2D1, C3D1, and progression. Targeted exome sequencing (TES) of ctDNA will track primary/resistant KIT mutation dynamics across therapy. 18 FDG PET/CTs are performed in 20 pts at b/l, C1D15, and C2D1, which guide a biopsy of a resistant tumor. TES, allele-specific and long-read PCR (to detect AP+AL mutation phasing), and immunoblotting (evaluating KIT pathway activation) will be performed on tissue. EORTC QLQ-C30 surveys collect pt-reported outcomes (PRO) at b/l, on treatment, and at progression. The primary endpoint is median progression-free survival (mPFS) and secondary endpoints include overall survival at 1 and 2 years, clinical benefit rate at 16 wk, adverse event rate, PRO, and KIT mutation profile in ctDNA and tissue. 35 evaluable pts achieves 83% power (p<0.05, one-sided) in a one-sample log-rank test to detect a mPFS of 6.5 mo vs 4 mo (historic control). Expected accrual is 12 mo across 4 sites in the United States with ~36 mo to study completion. Clinical trial information: NCT06208748 .

826 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2 nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2 nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .

11533 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .

TPS766 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations. In a Phase 1/2 clinical study, pts with relapsed and/or refractory GIST and a median of 3 prior lines of therapy treated with bezuclastinib + sunitinib (n=15) experienced clinical benefit and an acceptable safety profile, warranting further evaluation in a randomized trial. Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. The lead-in portion, to test a new formulation of bezuclastinib, (Part 1) has completed enrollment. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD has been determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated. Clinical trial information: NCT05208047 .

PURPOSE Multidisciplinary tumor boards (MTBs) support high-quality cancer care. Little is known about the impact of information technology (IT) tools on the operational and technical aspects of MTBs. The National Comprehensive Cancer Network EHR Oncology Advisory Group formed a workgroup to investigate the impact of IT tools such as EHRs and virtual conferencing on MTBs. METHODS The workgroup created a cross-sectional survey for oncology clinicians (eg, pathology, medical, surgical, radiation, etc) participating in MTBs at 31 National Comprehensive Cancer Network member institutions. A standard invitation e-mail was shared with each EHR Advisory Group Member with a hyperlink to the survey, and each member distributed the survey to MTB participants at their institution or identified the appropriate person at their institution to do so. The survey was open from February 26, 2022, to April 26, 2022. Descriptive statistics were applied in the analysis of responses, and a qualitative thematic analysis of open-ended responses was completed. RESULTS Individuals from 27 institutions participated. Almost all respondents (99%, n = 764 of 767) indicated that their MTBs had participants attending virtually. Most indicated increased attendance (69%, n = 514 of 741) after virtualization with the same or improved quality of discussion (75%, n = 557 of 741) compared with in-person MTBs. Several gaps between the current and ideal state emerged regarding EHR integration: 57% (n = 433 of 758) of respondents noted the importance of adding patients for MTB presentation via the EHR, but only 40% (n = 302 of 747) reported being able to do so most of the time. Similarly, 87% (n = 661 of 760) indicated the importance of documenting recommendations in the EHR, but only 53% (n = 394 of 746) reported this occurring routinely. CONCLUSION Major gaps include the lack of EHR integration for MTBs. Clinical workflows and EHR functionalities could be improved to further optimize EHRs for MTB management and documentation.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0–1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64−1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39−1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .