TPS5111 Background: Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease with high unmet need. Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is highly enriched in > 85% of prostate cancer (PC), 1 and prostate-specific membrane antigen (PSMA) expression is > 100-fold higher in patients (pts) with mCRPC. 2 These are well-established and actionable targets in mCRPC. ABBV-969, a dual variable domain IgG1 drug conjugate, targets STEAP1 and PSMA and includes a topoisomerase-1 inhibitor (Top1i) payload. Based on preclinical data, ABBV-969 is expected to have greater efficacy and wider activity than targeting either antigen alone. We describe a first-in-human study of ABBV-969 in pts with mCRPC. Methods: This phase 1 open-label study (NCT06318273) of ABBV-969 monotherapy evaluates safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Eligible pts, ≥ 18 years of age, have mCRPC treated with and progressed on ≥ 1 prior novel hormonal agent for mPC/CRPC and ≥ 1 taxane for PC (or have refused, are intolerant to, or unable to access taxanes). Pts must have a life expectancy > 6 months, serum testosterone levels ≤ 50 ng/dL, ≥ 1 metastatic lesion at baseline, and serum prostate-specific antigen (PSA) levels ≥ 1.0 ng/mL. Part 1 (dose escalation) of the study will enroll up to ~80 pts and is guided by the Bayesian optimal interval design primarily based on the dose-limiting toxicity rate. Part 2 (dose expansion) will randomize up to 60 pts in 2 (1:1) or 3 (1:1:1) dose levels (determined in part 1). Part 1 will enroll pts in US, Israel, Japan, and Australia with Canada, France, and Spain added in part 2. Optimal (recommended phase 2) dose will be determined by the totality of PK, PD, safety, and efficacy data. Pts will receive intravenous ABBV-969 until disease progression, intolerable toxicity, or other study discontinuation criteria are met. The study objectives and endpoints are shown in the Table. 1. Xu M, et al. Cancers 2022;14:4034. 2. Sweat SD, et al. Urology 1998;52:637–40. Clinical trial information: NCT06318273 . Objectives and endpoints. Objective Endpoint Primary Safety and tolerability Adverse events and dose-limiting toxicitiesClinical laboratory parameters, vital signs, ECG Secondary Preliminary efficacy Primary ≥ 50% prostate-specific antigen (PSA) decrease from baseline Secondary Confirmed complete response(CR)/partial response (PR) per RECIST v1.1PSA response durationDuration of response for pts with CR or PROverall survivalProgression-free survival Pharmacokinetic (PK) characterization PK parameters including C max , T max , t 1/2 , and area under the curve using noncompartmental methodsDetermination of antidrug antibodies Dose optimization Recommended phase 2 dose determined using all available information Previously presented at ESMO 2024, FPN: 1660TiP, Raanan Berger et al - reused with permission.

Amino Acid Sequence of AM-1 VH Region

Table S1: ABT-165 binding affinity; Table S2: ABT-165 in vitro potency; Table S3: Effect of VEGF on anti-DLL4 cellular potency of ABT-165; Table S4: Summary of in vivo efficacy; Table S5: Key safety findings of ABT-487 and ABT-165; Figure S1: Serum concentration-time profiles of ABT-165 in cynomolgus monkeys; Figure S2: Effect of antibody or antibody fragment valency on anti-DLL4 cellular potency; Figure S3: Effect of VEGF on the activity of DLL4 mAb and ABT-165 to downregulate DLL4 protein; Figure S4: Plasma levels of total soluble DLL4 and VEGF in cynomolgus monkeys after ABT-165 treatment.

Background: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/ CT images in patients with multiple myeloma (MM) to standardize FDG PET application.Methods: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD).Results: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. Conclusions: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6

Background: Therapeutic advances in multiple myeloma (MM) have greatly improved the rate and depth of response. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that has synergistic activity with carfilzomib (K) and dexamethasone (d), and is currently under investigation as a targeted therapy in relapsed/refractory (R/R) MM. Using next-generation sequencing (NGS) and 18F-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), we aimed to comprehensively evaluate minimal residual disease (MRD) in R/R MM patients (pts) treated with VenKd. Methods: In this phase 2, dose-escalation study (NCT02899052), R/R MM (1 - 3 prior lines of therapy and no prior K exposure) pts received VenKd: Ven 400 mg/day + K 27 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,8,15,22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 d1,8,15 + d 40 mg d1,8,15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,2,8,9,15,16,22,23 (Cohort 4). The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR and cytogenetic abnormalities by interphase fluorescence in situ hybridization. MRD assessments by NGS (clonoSEQ®) were performed on bone marrow aspirates at cycle 3 day 1 in pts achieving VGPR or better, time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR with negativity determined at <10-5 threshold. FDG-PET/CT imaging was performed on a subset of pts at baseline, cycle 3 day 1, and confirmation of CR or sCR, which corresponded to the bone marrow MRD evaluations by NGS. Lesions assessed by PET/CT were guided by standard of care imaging (i.e., x-ray, CT), and FDG-uptake was measured by maximum standardized uptake value. Pts were excluded from subsequent FDG-PET imaging based on proximity of evaluable lesions to anticipated areas of high normal FDG uptake (e.g., brain), or PET negative based on baseline FDG-PET imaging. MRD negativity (NGS and/or Imaging) was evaluated in the ITT population and key biomarker-defined subgroups (t(11;14) and BCL2high). Pts with missing or indeterminate assessments were considered MRD positive. Correlation with PFS, DOR, OS, and patient-reported outcomes (e.g., physical functioning, pain scores, fatigue) will be presented. Results: As of 14 Feb 2020, 49 pts were enrolled (4 in cohort 1, 3 in cohort 2, 7 in cohort 4 and 35 in cohort 3 + expansion). Pts had received a median of 2 (1-3) prior lines of therapy, 96% were exposed to PI (57% refractory), 90% exposed to IMiD (71% refractory), and 86% exposed to PI + IMiD (45% double refractory). Median age was 60 years (37 - 79), 61% had ISS II/III disease, 27% had t(11;14), and 45% were BCL2high. Of note, 8 out of the 22 (36.4%) BCL2high pts were t(11;14) positive. Overall response rate (ORR) was 80% (≥PR), including 65% ≥ VGPR and 41% ≥CR (Table 1). Among t(11;14) pts, ORR was 92%, ≥ VGPR 85%, and ≥CR 54%; while among BCL2high pts ORR was 86%, ≥ VGPR 77%, and ≥CR 41%. Of the 19 pts assessed for MRD by NGS, 15 (79%) had clonotypes identified at baseline. Of these 15 pts, 6 (40%) achieved MRD negativity (<10-5) by NGS in the bone marrow after VenKd treatment. Of the 12 pts who participated in the FDG-PET sub-study, 10 (83%) were FDG-PET positive at baseline, and 8 (67%) completed post-treatment FDG-PET imaging. Of these 8 pts, 3 (38%) achieved complete metabolic response (CMR) by FDG-PET imaging after VenKd treatment. While only 4 pts were evaluated concurrently for MRD by NGS and FDG-PET/CT imaging, the assessments were concordant for 3 pts (2 positive, 1 negative). The discordant result (NGS negative, FDG-PET/CT positive lymph node) indicated clearance of disease in the bone marrow while the presence of a potential soft tissue plasmacytoma remaining after treatment with VenKd. Of the 19 pts evaluated by either NGS or FDG-PET/CT, 8 (42%) achieved MRD negativity by NGS in the bone marrow or CMR by FDG-PET/CT after VenKd treatment. The highest rates of MRD negativity were observed in t(11;14) and BCL2high subgroups (Table). Conclusions: The combination of VenKd demonstrates promising efficacy in pts with R/R MM, including high rates of MRD, particularly in the t(11;14) and BCL2high subgroups. Overall, MRD assessments by NGS and FDG-PET/CT were highly concordant in this study and may be complementary for assessment of disease clearance in MM. Disclosures Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Burwick:AbbVie: Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Kaufman:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cabanillas:AbbVie: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Masud:AbbVie: Current Employment, Other: may hold stock or stock options . Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Bueno:AbbVie: Current Employment, Current equity holder in publicly-traded company. Mudd:AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Davies:Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cancer cells are highly dependent on NAD+/NADH produced via the nicotinamide salvage pathway. The rate-limiting enzyme in this pathway is the nicotinamide phosphoribosyltransferase (NAMPT), which we have targeted with novel NAMPT inhibitors. NAMPT inhibition elicits depletion of total cellular NAD+ levels and ultimately cytotoxicity via depletion of cellular ATP levels. 18F-fluorodeoxyglucose- positron emission tomography (FDG-PET) is a translational imaging tool to assess glucose utilization in tumors and normal tissue. We used FDG-PET to understand the timing of ATP depletion in vivo and better understand the pharmacology of NAMPT inhibitors. Because of the intimate relationship between cellular ATP levels and cell viability, we developed an in-depth understanding of our NAMPT inhibitor pharmacology and the relationship with changes in tumor FDG uptake. Taken together, we show that FDG-PET could be used as a biomarker in clinical studies to understand dose and provide proof of mechanism for NAMPT inhibitors. SIGNIFICANCE STATEMENT: Our imaging data suggest that tumor 18F-fluorodeoxyglucose uptake can provide insight into the ATP status inside the tumor after nicotinamide phosphoribosyltransferase (NAMPT) therapy, with a novel NAMPT inhibitor. Such an approach could be used clinically as a pharmacodynamic biomarker to help understand the implications of dose, schedule, rescue strategy, or other clinical biomarkers.

1025 Introduction: Bruton9s tyrosine kinase (BTK) is a key component of B-cell receptor signaling (BCR), and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B-cell malignancies and autoimmune disorders. Here we report for the first time the development of a novel BTK PET tracer with the potential for imaging of target expression and/or target engagement (by small molecule therapeutics). Methods: Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]ABBV-BTK1 with a 6% decay-corrected radiochemical yield, >3000 Ci/mmol specific activity, and a radiochemical purity of 99%.Following i.v. administration of [18F]ABBV-BTK1 (120±17 µCi, 0.084±0.05 µg) 60 minute dynamic images were acquired on an Inveon PET/CT system, in two xenograft models: REC-1 (n=6), an efficacious mantle cell lymphoma model, and U87MG (n=6), a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10 min prior to tracer injection) and displacement (30 min post-tracer injection) studies with a reversible BTK inhibitor to examine BTK binding. Regions of interest were manually delineated in the tumor and left ventricle and time activity curves were generated. Estimates of volume of distribution (VT) of the tracer (defined as the ratio of the tracer concentration in tumor (CT, kBq·cm-3) to that in plasma (CP, kBq·mL-1) at equilibrium) were obtained using a metabolite-corrected image-derived input function and kinetic modeling. Results: VT, representing uptake of [18F]ABBV-BTK1, was significantly higher in BTK expressing REC-1 tumors (4.0±1.6) than non-BTK expressing U87MG tumors (0.5±0.13). Administration of BTK inhibitors reduced [18F]ABBV-BTK1 binding in the REC-1 tumor model consistent with [18F]ABBV-BTK1 binding to BTK. Conclusions: [18F]ABBV-BTK1 is a promising PET tracer candidate for PET imaging of BTK. Additional experiments are being conducted to further characterize tracer binding in vivo and explore potential clinical applications including assessment of target engagement. [asterisk]Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 - 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory. At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts. The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table. Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd. Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer:Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman:Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Freise:AbbVie, Inc: Employment, Equity Ownership. Ross:AbbVie, Inc: Employment, Equity Ownership. Pesko:AbbVie, Inc: Employment, Equity Ownership. Munasinghe:AbbVie, Inc: Employment, Equity Ownership. Gudipati:AbbVie, Inc: Employment, Equity Ownership. Mudd:AbbVie, Inc: Employment, Equity Ownership. Bueno:AbbVie, Inc: Employment, Equity Ownership. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.

AbstractDepatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795–805. ©2018 AACR.

Tremendous breakthroughs are being made in cancer drug discovery and development. However, such breakthroughs come at a high financial cost. At a time when there is increasing pressure on drug pricing, in part because of increased life expectancy, it is more important than ever to drive new therapeutics towards patients as efficiently as possible. In this review we discuss the applications of molecular imaging in oncology drug development, with a focus on its ability to enable better early decision making, to increase efficiency and thereby to lower costs.

TPS8056 Background: A significant unmet need for multiple myeloma (MM) therapy remains as many patients eventually relapse after or become refractory to current treatment options. Investigation of novel agents and combinations in relapsed/refractory (R/R) patients are therefore critical to advance therapy and improve patient outcomes. Venetoclax is a potent, selective, orally bioavailable inhibitor of BCL-2. Combination of venetoclax with dexamethasone and bortezomib, a proteasome inhibitor that can inhibit MCL-1 indirectly via stabilizing the MCL-1-neutralizing protein NOXA, showed high rates of clinical response in a Phase 1 study. The mechanism of MCL-1 inhibition is thought to be a class effect of proteasome inhibitors. Given the clinical data supporting the combination of venetoclax with a proteasome inhibitor, this study will evaluate whether venetoclax combined with carfilzomib and dexamethasone can provide a well-tolerated and efficacious treatment option for R/R MM patients. Methods: This Phase 2, open-label study will assess the combination of venetoclax, carfilzomib, and dexamethasone in patients with R/R MM (NCT02899052). Primary objectives are to assess the safety and tolerability of this combination. Secondary objectives include evaluation of the pharmacokinetics of venetoclax and carfilzomib, preliminary efficacy of the combination (including overall response rate, very good partial response or better rate, progression-free survival, time to progression, and duration of response), and minimal residual disease (MRD) in bone marrow by next generation sequencing. Exploratory objectives will assess pharmacodynamic and predictive biomarkers, MRD by PET, pharmacogenetics, and patient-reported outcomes. Safety and pharmacokinetic profiles of the combination will be evaluated in initial dose escalation cohorts to determine appropriate doses of venetoclax and carfilzomib to be used with dexamethasone; a dose expansion phase will evaluate the safety and efficacy profiles of the combination based on selected doses. Study recruitment began in January 2017, with target enrollment of ~40 patients from 10–15 sites in the United States. Clinical trial information: NCT02899052.

PURPOSE:Zr-89 positron emission tomography (PET) is a valuable tool for understanding the biodistribution and pharmacokinetics of antibody-based therapeutics. We compared the image quality of Zr-89 PET and F-18 PET in the Siemens microPET Focus 220 preclinical scanner using different reconstruction methods.PROCEDURES:Image quality metrics were measured in various Zr-89 and F-18 PET phantoms, including the NEMA NU 4-2008 image quality phantom. Images were reconstructed using various algorithms.RESULTS:Zr-89 PET had greater image noise, inferior spatial resolution, and greater spillover than F-18 PET, but comparable recovery coefficients for cylinders of various diameters. Of the reconstruction methods, OSEM3D resulted in the lowest noise, highest recovery coefficients, best spatial resolution, but also the greatest spillover. Scatter correction results were found to be sensitive to varying object sizes.CONCLUSIONS:Zr-89 PET image quality was inferior to that of F-18, and no single reconstruction method was superior in all aspects of image quality.

The objective of this study was to determine the utility of (99m)Tc-3P-Arg-Gly-Asp (RGD2) single photon emission computed tomography (SPECT)/computed tomography (CT) for noninvasive monitoring of integrin αvβ3-expression response to antiangiogenic treatment with linifanib. Linifanib or vehicle therapy was carried out in female athymic nu/nu mice bearing U87MG glioma (high αvβ3 expression) or PC-3 prostate (low αvβ3 expression) tumors at 12.5 mg/kg twice daily. The average tumor volume was 180 ± 90 mm(3) the day prior to baseline SPECT/CT. Longitudinal (99m)Tc-3P-RGD2 SPECT/CT imaging was performed at baseline (-1 day) and days 1, 4, 11, and 18. Tumors were harvested at all imaging time points for histopathological analysis with H&E and immunohistochemistry. A significant difference in tumor volumes between vehicle- and linifanib-treated groups was observed after 4 days of linifanib therapy in the U87MG model. The percent injected dose (%ID) tumor uptake of (99m)Tc-3P-RGD2 peaked in the vehicle-treated group at day 11, while the %ID/cm(3) tumor uptake decreased slowly over the whole study period. During the first 2 days of linifanib treatment, a rapid decrease in both %ID/cm(3) tumor uptake and tumor/muscle ratios of (99m)Tc-3P-RGD2 was observed, followed by a slow decrease until day 18. No decrease in tumor uptake of (99m)Tc-3P-RGD2 or tumor volume was observed for either treatment group in the PC-3 model. Changes in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. Longitudinal imaging using (99m)Tc-3P-RGD2 SPECT/CT may be a useful tool for monitoring the downstream biologic effects of linifanib therapy.

ABT-414 is an antibody-drug conjugate (ADC) comprised of an anti-EGFR antibody (ABT-806) conjugated to the potent cytotoxic monomethylauristatin F. ABT-414 binds a unique epitope of EGFR which is largely inaccessible when EGFR is expressed at physiological levels but is accessible in tumors that express EGFRde2-7 [also referred to as EGFR variant III (EGFRvIII)] and in tumors with wild-type amplified EGFR or excessive wild-type EGFR activation. These properties of ABT-414 should limit the effects of the toxin on normal tissues. ABT-414 is highly effective in both mutant and wild-type EGFR-positive human tumor xenografts in mice producing complete regressions and cures observed in the most sensitive models. Squamous cell tumors display a relatively high expression of EGFR. Immunohistochemical analysis reveals >70% of squamous lung and esophageal cancers and >90% of oral cavity tumors show moderate to strong staining for EGFR. Given the high unmet need in these patients and the in vivo data supporting improved ABT-414 efficacy in tumors with high EGFR expression, a Phase I/IIa study evaluating the safety, pharmacokinetics and efficacy of ABT-414 in subjects with EGFR-positive, refractory solid tumors has been initiated with a phase IIa expansion at the MTD in squamous NSCLC. Additionally, this study will evaluate the use of SPECT imaging with an indium-111-labeled parental antibody (ABT-806i) as a predictive tool for patient response. Tumor uptake by ABT-806i SPECT imaging correlates with antitumor response in xenograft models, and ABT-806i has been shown to effectively target tumor sites in select cancer patients. A fluorescent in situ hybridization (FISH) probe to detect EGFR amplification and EGFR IHC are also being evaluated with the goal of identifying patients who are most likely to respond to ABT-414 treatment.Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A250.Citation Format: Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Peter J. Ansell, David R. Shalinsky, Yumin Zhang, Martin J. Voorbach, Sarah Mudd, Kyle D. Holen, Rod A. Humerickhouse, Edward B. Reilly. ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A250.

Abstract ABT-414 is an antibody-drug conjugate (ADC) comprised of an anti-EGFR antibody (ABT-806) conjugated to the potent cytotoxic monomethylauristatin F. ABT-414 binds a unique epitope of EGFR which is largely inaccessible when EGFR is expressed at physiological levels but is accessible in tumors that express EGFRde2-7 [also referred to as EGFR variant III (EGFRvIII)] and in tumors with wild-type amplified EGFR or excessive wild-type EGFR activation. These properties of ABT-414 should limit the effects of the toxin on normal tissues. ABT-414 is highly effective in both mutant and wild-type EGFR-positive human tumor xenografts in mice producing complete regressions and cures observed in the most sensitive models. Squamous cell tumors display a relatively high expression of EGFR. Immunohistochemical analysis reveals >70% of squamous lung and esophageal cancers and >90% of oral cavity tumors show moderate to strong staining for EGFR. Given the high unmet need in these patients and the in vivo data supporting improved ABT-414 efficacy in tumors with high EGFR expression, a Phase I/IIa study evaluating the safety, pharmacokinetics and efficacy of ABT-414 in subjects with EGFR-positive, refractory solid tumors has been initiated with a phase IIa expansion at the MTD in squamous NSCLC. Additionally, this study will evaluate the use of SPECT imaging with an indium-111-labeled parental antibody (ABT-806i) as a predictive tool for patient response. Tumor uptake by ABT-806i SPECT imaging correlates with antitumor response in xenograft models, and ABT-806i has been shown to effectively target tumor sites in select cancer patients. A fluorescent in situ hybridization (FISH) probe to detect EGFR amplification and EGFR IHC are also being evaluated with the goal of identifying patients who are most likely to respond to ABT-414 treatment. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A250. Citation Format: Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Peter J. Ansell, David R. Shalinsky, Yumin Zhang, Martin J. Voorbach, Sarah Mudd, Kyle D. Holen, Rod A. Humerickhouse, Edward B. Reilly. ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A250.