Ansell, Peter

Abstract Purpose: Our goal was to determine if the HRDefine biomarker combining methylation and mutation assessment of key homologous recombination repair genes identifies BRCA wildtype (BRCAwt) ovarian cancer (OC) with outcomes similar to BRCA mutated (BRCAm) OC within the context of a frontline PARP inhibitor trial for advanced ovarian cancer. Methods: We performed an exploratory biomarker analysis of blood and neoplastic samples from the VELIA trial, a phase 3 study evaluating the PARP inhibitor veliparib as frontline maintenance therapy in OC. We developed a highly sensitive droplet digital PCR assay for quantitative BRCA1 and RAD51C promoter methylation and assessed germline/somatic mutations using the BROCA next generation sequencing platform. Cases were grouped into: BRCAm, HRDefine positive (BRCAwt HRDefine+), and HRDefine negative (BRCAwt HRDefine-). Carcinomas were considered HRDefine+ if quantitative BRCA1 or RAD51C promoter methylation was >/= 60% or if a germline or somatic pathogenic variant (PV) was identified in the following non-BRCA HRR repair genes: RAD51C, RAD51D, PALB2, BARD1. For this analysis, the control group included the two study arms with placebo maintenance compared to the investigational arm of veliparib with chemotherapy and continued as maintenance (veliparib throughout group). HRDefine was compared to the Myriad genomic instability score (GIS) used as HRD assessment in the trial. Progression free survival (PFS) was compared using log rank tests. Results: Among 1140 VELIA participants, biomarker analysis could be performed for 487 cases. Of these, 255 (52%) were BRCAm, 60 (12%) were BRCAwt HRDefine+, and 172 (35%) were BRCAwt HRDefine-. BRCAwt HRDefine+ was driven by promoter methylation (57%), germline (40%), or somatic (3%) PVs. Median PFS (months, all arms combined) was 26 months (BRCAm), 27 months (BRCAwt HRDefine+), and 15 months (BRCAwt HRDefine-), with corresponding hazard ratios (HR) of 0.50 (95% CI: 0.39-0.65) and 0.50 (0.34-0.73) versus HRDefine-. All HRDefine+ molecular subgroups were associated with longer PFS, including RAD51C/D mutations (HR 0.44, 0.25-0.77) and promoter methylation (HR 0.60, 0.36-0.97). HRDefine positivity was significantly associated with improved PFS compared to HRDefine-/GIS low (n=60 vs n=111, median PFS 27 versus 14 months, HR 0.44, 0.30-0.65), while the HRDefine- cases with high GIS demonstrated a trend toward an intermediate PFS (n=56, median 18 months, HR 0.67, 0.45-1.01). When compared by treatment arm, median PFS was significantly longer in the veliparib throughout arm compared to control only for the BRCAm group (32 months vs 23 months, HR 0.61, 0.42-0.87), though the analysis was underpowered for the BRCAwt HRDefine+ sub-group (30 months vs 25 months, HR 0.79, 0.4-1.57). Conclusions: HRDefine identifies BRCAwt OC associated with a PFS that is like that of BRCAm cases and may improve stratification for PARP inhibitor therapy beyond current HRD assays. GIS may have some, albeit reduced, prognostic implication that is independent of HRDefine. Citation Format: Isabel V. Rodriguez, Marc Radke, Ronit Katz, Persephone Miller, Paula Ladd, Nithisha Khasnavis, Jennifer Ochoa, Melanie Dillon, Heather Lankes, Peter Ansell, Carol Aghajanian, Gini Fleming, Michael Birrer, Scott Kaufmann, Charles Leath, Kathleen Moore, Theresa Werner, Linda Van Le, Robert L. Coleman, Elizabeth M. Swisher. Application of HRDefine: a biomarker for identifying root causes of homologous recombination deficiency to a phase 3, randomized, placebo-controlled trial of veliparib in front-line treatment of advanced ovarian cancer (VELIA/GOG-3005) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A044.

PURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536 ) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Abstract Abstract 2617 Introduction: ABT-348 is a potent, novel, adenosine triphospate competitive inhibitor of Aurora A, B and C kinases. ABT-348 is also a potent inhibitor of all members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) families. ABT-348 has demonstrated strong antitumor activity in a variety of preclinical cancer cell line models, in vitro and in vivo, including leukemias as monotherapy and in combination with the DNA methyltransferase inhibitor, azacitidine. Objectives: The primary objectives of this study are to determine the safety and pharmacokinetics (PK) of orally and IV administered ABT-348 as monotherapy or in combination with azacitidine in patients (pts) with advanced hematologic malignancies. Secondary objectives include determination of the maximum tolerated dose (MTD) and exploration of biomarkers associated with ABT-348 activity. Methods: This phase 1 dose-escalation study of ABT-348 utilizes a modified continual reassessment method in pts with advanced hematologic malignancies: acute myelogenous leukemia (AML), acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia and myelodysplasia (MDS). Adult pts with histological or cytological confirmed disease, ECOG status 0–2, adequate hematological, renal and hepatic function and without significant hypertension or proteinuria are eligible. This study has four arms consisting of ABT-348 administered on a 28-day (D) cycle. Pts receive ABT-348 monotherapy once daily (QD, Arm A) or twice daily (BID; Arm B) on Days (D) 1, 8, and 15 of a 28-day cycle under fasting conditions. In Arm C, ABT-348 is given on the same schedule as Arm A in combination with azacitidine (75 mg/m2) administered IV or SC on Days 1 – 7 of each 28-day cycle. In Arm D, pts receive ABT-348 monotherapy on the same schedule as Arm A, but via IV administration. Samples are collected for PK and biomarker analyses. Pts are treated until progressive disease (PD) or unacceptable toxicity. Adverse event (AE) severity is graded using NCI-CTCAE v4.0. Results: 39 pts (median age, 66 y [45–86]) have enrolled (Arm A, n=32; Arm B, n=4; Arm C, n=3). Of these pts, 27 had AML, 11 had MDS and 1 had CML. Pts received a median of 4 prior therapies (range, 1 – 8). Best response to last prior therapy was: complete or partial response in 3 pts, stable disease in 11 pts, PD in 24, and not determined in 1. Dose escalation is shown in the table. The first dose-limiting toxicity (DLT) of grade 3 pancreatitis was observed at 640 mg in Arm A. Due to this DLT, along with a second case of grade 3 pancreatitis, further enrollment in Arm A was held and Arms B and C were opened. A DLT of grade 4 acute kidney injury was seen at 440 mg in Arm C. ABT-348-related AEs in greater than 2 pts were proteinuria (23%), nausea (21%), diarrhea (18%), hypertension (13%), vomiting (10%) and fatigue (8%). Grade 3/4 ABT-348-related AEs were hypertension (13%), pancreatitis (5%), acute kidney injury (3%) and diarrhea (3%). One patient in Arm A achieved a CRi (640 mg). Five of 32 pts in Arm A were treated for ≥4 cycles, including 2 of 7 pts at ABT-348 doses ≥ 640 mg. Based on preliminary PK analyses, Cmax and AUC of ABT-348 were approximately dose proportional in the dose range studied (10–690 mg); co-administration of azacitidine had no apparent effect on ABT-348 PK. Evidence of dual aurora/VEGF receptor kinase inhibition has been demonstrated by induction of polyploidy and PlGF, respectively. 33 pts have discontinued and 6 remain on study. Conclusions: ABT-348 has demonstrated on-target biomarker and clinical activity in pts with advanced hematologic magnancies, and was well tolerated at doses below 640 mg in Arm A. PK appears to be dose-proportional. Dose escalation is ongoing in Arms B and C (with azacitidine); an IV formulation of ABT-348 will also be evaluated. Disclosures: Off Label Use: Clofarabine in AML. Tibes:Abbott: Research Funding. Chiu:Abbott: Employment, Owns stocks Other. Xiong:Abbott: Employment, own Abbott stock Other. Qin:Abbott: Employment. Ansell:Abbott: Employment, own Abbott stock Other. Albert:Abbott: Employment, own Abbott stock Other. Tse:Abbott: Employment, own Abbott stock Other. Oliver:Abbott: Employment, own Abbott stock Other. Sajwani:Abbott: Employment, own Abbott stocks and participated in study design, data collection, analysis, interpretation and reviewing approving study documents related to ABT-348 programs. Other. McKee:Abbott: Employment, own Abbott stocks Other. Ricker:Abbott: Employment, own Abbott stocks Other.