Anthony W Tolcher

• South Texas Accelerated Research Therapeutics

Background The clinical utility of MEK inhibitors is limited to BRAF V600X mutant cancers and NF1 mutant neurofibromas due to early emergence of resistance and low therapeutic indices. IK-595, a novel MEK-RAF molecular glue, traps MEK in an inactive complex with all RAF isoforms and durably blocks MEK and ERK phosphorylation. IK-595 overcomes the k...

Background Targeting intrinsic and extrinsic metabolic pathways to leverage the body’s natural immune response mechanisms is of high interest in the fight against cancer. The polyamine pathway represents a potential target for novel antitumor therapies, as polyamine synthesis is dysregulated in various cancer types and high polyamine levels are oft...

Background Tumor cell hypersialylation is immune suppressive and associated with poor outcomes in cancer patients. E-602 is a first-in-class fusion protein of engineered human sialidase (Neu2) and IgG1fusion that cleaves sialic acids from sialoglycans on immune and tumor cells, alleviating immune suppressive mechanisms. In Phase 1, E-602 monotherap...

Background Decoupling dose-dependent efficacy from toxicity of anti-CTLA-4 therapies is essential to enable enhanced TI and efficacy. ADG116, an IgG1 monoclonal antibody targeting a unique epitope of CTLA-4 which is conserved across species, has demonstrated improved TI over ipilimumab via enhanced epitope-dependent ADCC and T cell priming. Muzasto...

Purpose: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 cl...

e14504 Background: HB0036 is a bispecific IgG1 antibody targeting both human programmed death ligand 1 (PD-L1) and the T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). Here we report the initial results from the first-in human study ofHB0036 in patients with advanced malignancies. Methods: This is a first-in-human, phase I/II, mul...

2612 Background: Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases orchestrate the DNA damage response. A synthetic lethal relationship between ATR and ATM genes in cancer has been described ¹ and ATMi synergistically potentiate the efficacy of ATRi in vitro and in vivo. ² The combination of tuvusertib + lartesertib was inv...

2614 Background: Ataxia telangiectasia and Rad3-related protein (ATR) kinase is critical in the DNA damage response, and its inhibition modulates antitumor immunity. The combination of ATR inhibitor (ATRi) + immune checkpoint inhibitor (ICI) has shown activity in patients with ICI-resistant tumors and may have the potential to overcome ICI resistan...

2529 Background: Activation of T cells in the tumor microenvironment by 4-1BB agonist antibodies is a promising approach to augment PD-(L)1 inhibitor efficacy. Ragistomig(ABL503/TJ-L14B) is a bispecific antibody combining PD-L1 antagonist with 4-1BB agonistic activity, designed to induce 4-1BB signaling only when bound to the PD-L1 tumor antigen on...

2521 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory re...

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 fol...

8617 Background: Dato-DXd is an antibody-drug conjugate (ADC) composed of an anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. We report updated findings from TROPION-Lung02 (NCT04526691) evaluating Dato-DXd plus pembro with or without Pt-CT as 1L therapy for aNSCLC. Methods: Patients (Pts) received Dato-DXd (4 or...

2613 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance may emerge in some of the patients treated. VEGF and TGF-β pathways play an important role in the development and function of the tumor-microenvironment (TME), contributing to be the immunosuppressive. TU2218 is a highly potent, or...

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and lo...

PURPOSE Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS TROPION-PanTumor01 (ClinicalTrials.gov id...

Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases are critical in the DNA damage response. ATR and ATM genes have a synthetic lethal relationship in cancer and ATMi synergistically potentiates the efficacy of ATRi in vitro and in vivo. Here, we studied the combination potential of the highly potent, oral agents tuvusertib a...

Background: ASTX295 is a novel small molecule antagonist of human Murine Double Minute 2 (MDM2), which tightly regulates the level and activity of the p53 tumor suppressor. To minimize potential thrombocytopenia previously seen with antagonism of this target, ASTX295 was designed to have a short half-life (t1/2) with decreased bone marrow (BM) expo...

Purpose Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary effica...

TPS237 Background: There is a high unmet need for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that has progressed on novel hormonal therapies (NHTs) due to acquired resistance to treatment. Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor and initiates the extrinsic coagulation c...

Purpose GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell–mediated antitumor activity in cancer patients. This phase Ib open-label study assesse...

TPS421 Background: Patients (pts) with metastatic pancreatic and esophageal cancers have poor prognosis, with 5-year survival rates of 3% and 6%, respectively (SEER 22). Tissue factor (TF), a factor VIIa receptor involved in initiation of the extrinsic coagulation cascade, is overexpressed in these tumors and has been associated with poor outcomes....

487 Background: Outcomes remain poor for pts treated with standard-of-care chemotherapy for advanced biliary tract cancer (BTC). Hence, there is a clinical need for novel therapeutic strategies. One such emerging strategy is antagonism of mouse double minute 2 (MDM2), which is amplified in 5–8% of cases of BTC. Brigimadlin (BI 907828) is a MDM2–p53...

Background Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pat...

Background: Mutations in the TP53 gene leading to p53 inactivation are the most common mutational event across human cancers. PC14586 is a first-in-class p53 reactivator that selectively binds to the mutated p53 Y220C protein and restores p53 wild-type activity. Preclinical data support potential for activity of PC14586 across TP53 Y220C-bearing tu...

Background Fibronectin (FN) is a ubiquitously expressed, high-molecular weight, extracellular matrix glycoprotein. The extra domain B splice variant of FN (EDB+FN) is a novel therapeutic target that is upregulated in the tumor microenvironment (TME) of multiple solid tumor types with restricted expression in normal tissues. PYX-201 is an investigat...

Background 4–1BB is a costimulatory receptor upregulated on tumor-infiltrating lymphocytes. 4–1BB signaling promotes T-cell proliferation and activation and decreases T-cell exhaustion. 4–1BB agonists have shown promising antitumor activity but have been limited by hepatotoxicity resulting from systemic 4–1BB activation.INBRX-105 is a 4–1BB×PD-L1 b...

Background Anti-programmed cell death-1 (PD-1)/PD ligand 1 (PD-L1) checkpoint blockade has not been effective for all solid tumors and alternative therapies are needed for patients who do not respond to currently approved checkpoint inhibitors. Sialic acid binding immunoglobulin like lectin-15 (Siglec-15) is an immunomodulatory pathway independent...

Background OX40 is a member of the TNF receptor superfamily and a key costimulatory molecule. OX40 signaling can increase T-cell survival, augment clonal expansion of antigen-specific effector and memory T-cell populations, and inhibit regulatory T-cell–induced immunosuppression, making it an attractive therapeutic target. The endogenous trimeric O...

Background TU2218 is a highly potent, oral dual inhibitor against TGFβ type I receptor (TGFβRI/ALK5) and VEGFR2. VEGF and TGF-β pathways play important roles in the function of TME, especially in immune tolerance inextricably related with poor outcomes of anti-PD-(L)1 therapy. This is a first-in-human study to investigate the safety and tolerabilit...

Purpose: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC). Patients and methods: A...

TPS3159 Background: ELU001 is a novel first-in-class nanoparticle drug conjugate that consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol cha...

3002 Background: Small cell lung cancer (SCLC) has a dismal prognosis and new therapies are urgently needed. SEZ6 is a transmembrane protein expressed in SCLC tumors that may be used as a therapeutic target. ABBV-011 is an antibody-drug conjugate (ADC) targeting SEZ6 with a calicheamicin payload, which has shown antitumor activity in preclinical mo...

2589 Background: HB0025 is a recombinant humanized anti-PD-L1 monoclonal antibody-VEGFR1 fusion Protein. Nonclinical data both in vitro and vivo have shown high-affinity binding to both targets as well as the inhibition of tumor growth in animal models. Here, we present preliminary safety and efficacy data from a dose escalation phase I study of HB...

9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable...

2524 Background: We present results from the completely enrolled monotherapy arm of the first-in-human dose escalation study of AGEN2373, a novel CD137 agonist antibody engineered to maximize efficacy by circumventing the dose-limiting hepatotoxicity reported for prior CD137 agonists (NCT04121676). AGEN2373 binds to a unique epitope of CD137 on eff...

2531 Background: TST005 is a novel bi-functional fusion protein combining a high affinity PD-L1 mAb and a differentiated TGF-β trap with improved stability. In pre-clinical study, TST005 showed no antibody-dependent dependent cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) activity. Methods: This is a Phase 1, dose escalation study w...

3084 Background: Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK pathways. Targeting multiple pathways could lead to more effective therapy than agents inhibiting single downstre...

9559 Background: Alrizomadlin is a novel, orally active small-molecule MDM2 inhibitor that activates p53-mediated apoptosis in tumor cells, also functions as a host immunomodulator, and may restore antitumor activity in patients with cancer that has progressed on PD-1/PD-L1 inhibitors. Alrizomadlin is currently being investigated for treatment of p...

3087 Background: Tumor-targeted drug delivery technologies are urgently needed to overcome conventional chemotherapy’s lack of tumor selectivity. Alphalex conjugates, which contain a pH-low insertion peptide (pHLIP), a linker and a payload, are designed to overcome this lack of selectivity. Unlike antibody drug conjugates, alphalex PDCs target tumo...

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated d...

Background: Inactivation of the Hippo pathway is a common finding in MM and other cancers, leading to constitutive YAP activation, but has thus far been undruggable. NF2 encodes Merlin that activates Hippo kinase resulting in inactivation of YAP, which is the major effector of Hippo signaling. NF2-deficient tumors, often due to inactivating NF2 mut...

Background: ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody® with a masking peptide blocking the antigen binding site. ADG126 is designed to be preferentially activated in the tumor microenvironment (TME), with the goal of limiting on-target off-tumor toxicities and promoting prolonged exposure to active drug in the TME. Activated ADG126 binds t...

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated as monotherapy in Part A1 of the first-in-human open-label, single-arm study (NCT04170153). M1774 was wel...

M4076 is a potent and selective oral inhibitor of ataxia-telangiectasia mutated (ATM), a key kinase of the DNA damage response (DDR) involved in double-strand break repair. Preclinically, M4076 when combined with DNA damage-inducing therapy or other DDR inhibitors caused unrestricted cell cycle progression and DNA damage accumulation, resulting in...

Aim: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors. Methods: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologicall...

Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective phosphoinositide-3-kinase (PI3K)-γ inhibitor with anti-tumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Onco...

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 mAb covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor selective, tetrapeptide-based cleavable linker. Dato-DXd has previously shown encouraging activity in heavily pretreated p...

543 Background: Standard-of-care treatment for advanced biliary tract cancer (BTC) is chemotherapy and outcomes remain poor; hence, there is a clinical need for effective targeted treatments. As MDM2 is a negative regulator of the tumor suppressor p53, blocking the MDM2–p53 interaction is a potential antitumor strategy. Further, preliminary data in...

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recrui...

Purpose. Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced...

3095 Background: Preclinical data show that combining a murine double minute 2–tumor protein 53 (MDM2–p53) antagonist with immune checkpoint inhibitors produces anti-tumor effects in multiple tumor types. This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, a MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type...

TPS1122 Background: Various cancers evade apoptosis by overexpressing BCL-2 proteins. Investigational agent lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor, while palbociclib inhibits cyclin-dependent kinases (CDK) 4 and 6. In preclinical studies, palbociclib decreased proliferation of ER ⁺ breast cancer cell lines by arresting...

9517 Background: Alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in pts with cancers that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial eva...

e17601 Background: SAFEbody ADG126, a masked version of NEObody ADG116 (ESMO IO Conference Abstract #394, NCT04501276), targets a unique species-conserved CTLA-4 epitope with preclinical safety and efficacy profiles superior to ipilimumab, an approved anti-CTLA-4 immune checkpoint inhibitor known to cause treatment-related irAEs in ̃70% of patients...

2505 Background: Immunoglobulin-like transcript 3 (ILT3) is an inhibitory receptor associated with immune tolerance and T-cell suppression within the tumor microenvironment. MK-0482, a novel humanized IgG4 mAb targeting ILT3, is undergoing phase 1 evaluation ± pembrolizumab (pembro) in advanced solid tumors (NCT03918278; MK-0482-001). Dose escalati...

TPS3178 Background: Autophagy, a catabolic process to resupply nutrients and recycle damaged organelles, is activated by cancer cells to survive hypoxia, limited nutrients, or chemotherapy. The RAS family of oncoproteins are the most commonly mutated oncoproteins in human cancer and require autophagy for tumor growth and survival. RAS activates sig...

2566 Background: We have previously shown that systemic administration of GS-3583, a Fms-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein leads to expansion of conventional dendritic cells (cDC), both subtype 1 (cDC1) and subtype 2 (cDC2), in the periphery of healthy volunteers (Rajakumaraswamy N, et al. J Clin Oncol. 2021;39[suppl_15]:2559....

3003 Background: The p53 tumor suppressor protein is a transcription factor that acts to maintain genome stability in response to cellular stress. Spontaneous mutation of the TP53 gene leading to inactivation of the p53 protein is the most common mutational event across all human cancers. PC14586 is a novel, small molecule structural corrector that...

TPS3168 Background: The transcriptional enhanced associate domain (TEAD) family of proteins are key transcription factors in the Hippo signaling pathway and play a critical role in cell proliferation, migration, angiogenesis, and apoptosis. Published literature demonstrates that approximately 10% of all solid tumors present with a dysregulated Hipp...

TPS2693 Background: M2-like macrophages are thought to promote an immunoinhibitory environment and prevent activation and proliferation of T cells, leading to resistance to checkpoint inhibitor (CPI) therapy. OR2805 is a fully human monoclonal antibody identified in a patient who had an exceptional response to CPI. OR2805 recognizes CD163, an immun...

TPS3158 Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ̃12 folic acid targeting moieties and ̃22 exatecan topoisomerase-1 inhibitor payloads on Cathepsin-B cleavable linkers covalently bound to the surface of each silicon core/polyethylene glycol C’Dot nanoparticle....

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell...

Background Tumor-targeted drug delivery technologies are urgently needed to overcome the lack of tumor selectivity, a major drawback of conventional chemotherapy. In addition, the acidic intercellular microenvironment in solid tumors traps weak acid/base chemotherapy agents, preventing necessary intracellular concentrations in tumour cells. An alph...

Background Siglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins involved in immune regulation. NC318 is a first-in-class humanized IgG1κ monoclonal antibody that blocks S15-mediated immune suppression. Methods The Phase 1 dose-escalation study was a classical 3+3 design in 15 tumor types (n=49). Phase 2 (n=47) wa...

Purpose: MPS1 kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase 1 study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Experimental design: Patients with solid tumors were randomized to receive oral BAY (BID 2‑days‑on/5‑days‑of...

Dysregulation of alternative pre-mRNA splicing has been identified as a common mechanistic driver of tumor initiation, disease progression, and emergence of therapy resistance. An iterative screening campaign identified SM08502, a potent pan-inhibitor of CDC-like kinases (CLKs), which are known to regulate alternative splicing. In preclinical studi...

Purpose: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922). Experimental design: Patients received PF-06647020 IV every 3 weeks (Q3W) at 0.2-3.7 mg/kg or Q2W at 2.1-3.2 mg/k...

TPS1108 Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed during embryonic development, but is minimally present or absent on post-partum healthy tissues. ROR1 is expressed in a variety of hematological and solid tumors and is associated with aggressive cancer phenotype and poor clinical outcomes. NBE-002 is...

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we r...

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-X L (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without...

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that bi...

3019 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates known to be dysregulated in cancer, including components of the spliceosome machinery. PF-06939999 is a selective small-molecule inhibitor of PRMT5. Here we report the safety, PK, PD, and preliminary activity of PF-06939999 in patients (pts) with selected a...

TPS3153 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response by sensing and responding to DNA replication stress, and by inducing cell cycle arrest to prevent aberrant replication and mitotic catastrophe. Based on extensive preclinical and limited clinical evidence, ATR inhibition...

2506 Background: Alrizomadlin (APG-115) restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and hence may restore antitumor activity in pts with cancers failing PD-1/PD-L1 blockade. Methods: This US multicenter trial assessed al...

2634 Background: CD137 is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator of both adaptive and innate immune cells, thus making it an attractive target for cancer immunotherapy. The development of first-generation anti-CD137 antibodies has been hampered by limited clinical activity or dose-limitin...

2553 Background: ORIC-101 is a potent and selective, orally bioavailable, small molecule antagonist of the glucocorticoid receptor (GR). Preclinical studies have demonstrated that activation of GR signaling leads to decreased responsiveness to chemotherapeutics (eg, taxanes) and antiandrogens across multiple tumor types. Mechanistically, ORIC-101 i...

Purpose: Leucine rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjug...

Background CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodula...

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with al...

Background: Immunosuppressive tumor associated macrophages (TAMs) have been shown to correlate with poor prognosis. SNDX-6352 is a humanized, high-affinity monoclonal IgG4 antibody that blocks dual ligand activation of colony stimulating factor- 1 receptor (CSF-1R), which regulates monocyte migration, proliferation and differentiation into TAMs. By...

Antagonist antibodies targeting immune checkpoint co-inhibitory receptor such as PD-1/PD-L1 have achieved great clinical success in cancer immunotherapy. However, agonistic antibodies targeting the co-stimulatory T cell receptors in the TNFR superfamily, and CD137 in particular, has suffered significant setback due to either dose-dependent severe l...

Background: Tumor associated macrophages have been proposed to suppress the anti-tumor immune responses potentiated by immune checkpoint blockade. CSF1 receptor (CSF-1R) blockade enhances anti-PD1 or PD-L1 anti-tumor efficacy in various tumor models. SNDX-6352 is a high affinity, humanized monoclonal antibody against CSF1R. This Phase 1 study was d...

3512 Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib...

TPS3166 Background: Siglec-15 (S15) is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct subgroup of immunoglobulin (Ig) superfamily proteins involved in discriminating self from non-self-immune regulation (Macauley MS et al. 2014). Nonclinical models demonstrate S15 mediates suppression of T cell proliferation...

TPS3660 Background: Preclinical data show that the combination of a murine double minute 2–tumor protein 53 (MDM2–TP53) antagonist with anti-PD-1 and anti-LAG3 antibodies produces an anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended dose for expansion (RDE), and preliminary efficacy of BI 90...

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536...

Background PF-06650808 is a novel anti-Notch3 antibody–drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients...

Purpose: This first-in-human, phase 1 study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Experimental design: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a...

Background: Currently, no therapies are approved specifically for EGFR-overexpressing tumors. AVID100 is a novel anti-EGFR antibody drug conjugate (ADC, DM1 payload) that was rationally designed for anti-tumor efficacy without accompanying on-target, off-tumor toxicity by employing an EGFR function-blocking antibody moiety. Although EGFR is overexp...

Keywords: MDM2; Immuno-oncology; PD-1 Background APG-115 is an orally active small-molecule MDM2 inhibitor that potently binds MDM2 protein, restores TP53 function, and activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T ce...

Background: The oncogenic mitogen-activated protein kinase (MAPK) pathway is dysregulated in a broad range of cancers through mutations in BRAF, KRAS, NRAS, HRAS and MEK1 genes. ASN007 is a novel, potent and orally bioavailable inhibitor of ERK1/2 kinases (IC50 1-2nM) with a very long target residence time (550 min). Preclinical studies show strong...

Background: Ligation of CD137 induces a co-stimulatory signal on activated CD8+ T cells and natural killer (NK) cells, resulting in proliferation, increased pro-inflammatory cytokine secretion and cytolytic function. ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody; ADG106 targets a unique epitope of CD137 with novel mechanism...

Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tar...

TPS2666 Background: Rebastinib is a potent, orally administered, kinase switch control inhibitor selectively targeting the tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells and has critical roles in angiogenesis. In addition, TIE2 is highly expressed in a subset of macrophages, TIE2-expressing macrophag...

3010 Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated...

3004 Background: ABBV-085 is an ADC (conjugated to monomethyl auristatin E, drug:antibody ratio of 2:1) directed against leucine-rich repeat containing 15 (LRRC15), a type 1 transmembrane protein highly expressed on the surface of sarcomas and cancer-associated fibroblasts in stroma of many other cancers. ABBV-085 induced antitumor activity in both...

Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalatio...