Jones, Robin L.

11506 Background: Catequentinib Hydrochloride (AL3818, Anlotinib, Catequentinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. There remains an unmet need for effective, well tolerated therapies for patients (pts) with advanced/ metastatic leiomyosarcoma (LMS). We performed a randomized, double blind trial of Catequentinib monotherapy versus placebo in advanced/metastatic LMS. Methods: Patients with a diagnosis of LMS requiring third or further line treatment were eligible. Catequentinib was administered in a 21-day cycle with 14 days on and 7 days off regimen. In this double blind phase 3 trial, patients were randomized 2:1 to Catequentinib or placebo, with the option of crossover to Catequentinib after confirmed Progression Disease (PD) on placebo. Progression-free survival (PFS) with Log Rank test was the primary endpoint and the trial was conducted at multiple sites in the US, UK and EU. Results: Total N = 111 patients were enrolled, and N = 110 were treated and evaluated, 74 randomized to Catequentinib (C), and 36 to placebo (P). In arms (C)/(P) median ages were 59.0/60.5 (range: 33-91) years respectively and 59/29 (79.7%/80.6%) were female. Median PFS by Blinded Independent Central Review (BICR) met the primary endpoint at 3.42 months (95% CI: 2.60, 6.83) for (C) and 1.41 months (95% CI: 1.35, 4.86) for (P) with a p-value of 0.0265 and a HR of 0.536 (95% CI: 0.307, 0.936). Median PFS for patients stratified at ≤ 3 prior lines was 4.86 months (95% CI: 2.04, 8.94) for (C) and 1.41 months (95% CI: 1.31, 4.86) for (P) with a p-value of 0.0046 and a HR of 0.386 (95% CI: 0.196, 0.760). The 6-month progression-free rate was 42.37% for (C) and 20.71% for (P). OS was 17.45 months (95% CI: 13.57, 19.32) for (C) and 16.33 months (95% CI: 11.27, NE) for crossover patients in the (P) arm. 30 (40.5%) of patients have experienced grade 3 treatment-related adverse events in the (C) arm compared to 3 (8.3%) of patients in the (P) arm. The most common TEAE for (C) vs (P) were diarrhea (50.0% vs 22.2%), stomatitis (31.1% vs 8.3%), fatigue (64.9% vs 41.7%), and hypertension (47.3% vs 19.4%). Conclusions: This phase 3 trial met the primary PFS endpoint and demonstrates superior PFS for Catequentinib vs placebo in metastatic/advanced LMS. This study confirms the acceptable benefit-risk profile of Catequentinib in LMS. Catequentinib is an effective and well tolerated treatment option for patients with LMS. Clinical trial information: NCT03016819 .

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is a disease with guarded prognosis with a 5-year overall survival (OS) of 3.1% in patients with metastatic disease. The need for innovative treatments for this lethal disease is paramount. TTFields is a novel treatment modality that employs low intensity, alternating, and intermediate frequency electrical fields that abrogates cancer cell proliferation through different mechanisms. These include inhibition of mitosis, disruption of cancer cell membranes, metabolomic dysregulation of cancer cells, and immunogenic activation of the tumor microenvironment (TME). TTFields are approved in glioblastoma multiforme, non-small cell lung cancer and malignant mesothelioma. The PANOVA trial demonstrated promising efficacy for TTFields plus chemotherapy in patients with PDA. A trial of GCN in patients with PDA demonstrated exceptional efficacy in patients with metastatic disease. Here in, we present our ongoing clinical trial investigating the safety and efficacy of TTFields plus GCN in patients with PDA (NCT04605913). Methods: This a phase I/II trial with an initial safety run-in phase followed by the phase II portion. The primary objective of the trial is to determine the safety (CTCAE v 5.0) of GCN plus TTFields. Secondary objectives include determining the 6-month progression free survival (PFS) rate, overall response rate (ORR, RECIST v1.1), 12-month survival rate, OS, and QOL (EORTC QLQ-C30, version 3.0.2.3). Inclusion criteria include PDA with liver metastasis (patients can have additional sites of metastasis), ECOG 0-1, measurable disease, and ability to operate the Novo TTF-100L (P)/Novo TTF-200T system. Treatment consisted of TTFields (150 kHz 18 hours/day) and GCN (G: 1000 mg/m2, C 30 mg/m2, and N: 150 mg/m2 every 2 weeks, 28 days cycle), followed by a maintenance phase after 6 months (G: 1000 mg/m2 every 2 weeks) plus TTFields until progression. Six patients were to be enrolled in the phase I portion and if ≤1/6 patients experienced a dose limiting toxicity (DLT, treatment emergent adverse event, or skin toxicity of Gr4), the plan would be to move to a phase II trial enrolling 34 more patients. If 2/6 patients experienced a DLT, 6 patients would be enrolled in dose level -1 (GCN plus TTFields for 9 hours/day followed by the maintenance treatment) and if tolerated the phase II portion would start with dose level -1 regimen. The phase I portion was completed without any DLTs and the trial is currently enrolling to the phase II portion. The total number of patients (40) was powered to the 6-months PFS rate and ORR (estimated using the lower bound of exact one-sided 90% confidence intervals). The goal is to "reject" a 6-month PFS rate of 66% and an ORR of 71% (based on previous GCN trial). Time-to-event endpoints will be assessed using the Kaplan-Meier method. Citation Format: Hani M. Babiker, Jason Starr, Jeremy Jones, Conor O’Donnell, Robert Jones, Jacqueline Boni, Lashundra Stewart, Josh Cameron, Oudom Kour, Kabir Mody, Robert R. McWilliams, Daniel H. Ahn, Tanios Bekaii-Saab, Mitesh J. Borad, Umair Majeed. A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT190.

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 .

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]

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.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA (ctDNA) next-generation sequencing (NGS) analysis from INTRIGUE showed pts with second-line advanced GIST with primary KIT exon 11 mutations and secondary resistance mutations exclusively in KIT exons 17/18 derived clinical benefit from ripretinib but not sunitinib (Bauer S et al. J Clin Oncol. 2023; Abs 397784). Outcomes in pts with advanced GIST with ctDNA not detected (ctDNA-ND) had not been evaluated. Here, we present exploratory data from INTRIGUE in pts who had baseline ctDNA-ND vs ctDNA detected (ctDNA-D). Methods: INTRIGUE is an open-label, phase 3 study that enrolled pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and stratified by mutation according to local pathology report. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA NGS-based assay. Pts with ctDNA-D had ≥1 somatic alteration in the 74 genes analyzed. Results: Pts with ctDNA-ND (82/362, 22.7%) were younger (median: 55.5 vs 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11–459] vs 108.8 [15–418] mm) vs ctDNA-D (280/362, 77.3%). Progression-free survival (PFS) was longer in pts with ctDNA-ND vs ctDNA-D and numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND (Table). Pts with ctDNA-ND categorized as not having a KIT exon 9 mutation at randomization ( KIT exon 11, other KIT/PDGFRA, or KIT/PDGFRA wild-type; n = 71) had longer PFS with ripretinib vs sunitinib (median not estimable [NE] vs 11 months; HR = 0.56; 95% CI 0.28 to 1.12). Objective response rate (ORR) and overall survival (OS) were higher with ctDNA-ND vs ctDNA-D. Safety was similar between groups and consistent with the primary analysis. Conclusions: Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501 . [Table: see text]

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501 ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/ platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.