EXPLORE BIOMARKERS

Nectin-4 is a type I transmembrane protein and a member of the nectin glycoprotein family.¹ Nectin-4 is primarily expressed in the placenta during fetal development and is weakly expressed in some adult human tissues, such as skin.^1,2 Overexpression of Nectin-4 has been observed in several solid tumor types including urothelial, breast, cervix, lung, and ovarian cancers,^2,3 and is associated with promoting tumor proliferation and metastasis.¹ The higher expression of Nectin-4 in tumor cells compared to normal cells makes the protein an ideal target for tumor-specific delivery of cytotoxic agents via an antibody-drug conjugate (ADC).¹

LY4052031 and LY4101174 are a next-generation anti-Nectin-4 targeting ADCs. LY4052031 is comprised of a human IgG1 Fc-silent monoclonal Nectin-4 antibody linked to a novel camptothecin (topoisomerase I inhibitor) payload, via a cleavable linker with a homogeneous drug-antibody ratio (DAR) of 8:1.⁴ LY4101174 is comprised of a humanized IgG1 Fc-silent monoclonal Nectin-4 antibody linked to the topoisomerase I inhibitor, exatecan, via a maleimide-B-glucuronide poly-sarcosine linker with a homogeneous drug-antibody ratio (DAR) of 8:1.² In preclinical in vivo models, LY4052031 and LY4101174 have shown antitumor activity across a range of Nectin-4 expression levels including a Nectin-4 MMAE ADC resistant model.^2,4

Currently, biomarker testing is not necessary to identify eligible patients.

LY4052031 and LY4101174 are being investigated in global open-label, multicenter, phase 1a/1b studies in patients with advanced or metastatic urothelial carcinoma and select solid tumors. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein with very limited expression in normal tissues and substantial upregulation in prostate cancer.¹ Expression tends to increase with increasing pathological Gleason grades and is further upregulated with the emergence of androgen resistance.^2,3 Upon binding to a ligand, PSMA internalizes, thereby facilitating endocytosis and intracellular accumulation of PSMA-targeted compounds.⁴

[Ac-225]-PSMA-62 is a next-generation PSMA-targeting radioligand comprised of the alpha-emitting radioisotope actinium-225, a chelating moiety, linker region, and PSMA-62, a small molecule PSMA inhibitor. In nonclinical models, PSMA-62 showed high PSMA binding affinity, increased cellular internalization, and improved biodistribution, including high tumor retention and rapid renal clearance.⁵

Currently, biomarker testing is not necessary to identify eligible patients. However, dosimetry (PSMA-PET) may be needed to identify appropriate patients.

[Ac-225]-PSMA-62 is being studied in a phase 1/2 clinical trial for patients with metastatic castration-resistant prostate cancer and patients with biochemically recurrent prostate cancer. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Folate receptor alpha (FRα) is a cell-surface glycoprotein encoded by the gene FOLR1. It binds to folic acid and reduced folates with high affinity.^1,2 Upon binding, the receptor-ligand complex is internalized via potocytosis and fused with a lysosome, releasing the folate for use in reactions.² The expression of FRα in non-malignant tissues is limited, whereas it is overexpressed in many solid tumors such as ovarian, non-small cell lung, and colorectal cancers,³ making the receptor an attractive therapeutic target for these indications.^1,4

LY4170156 is an FRα-targeting antibody-drug conjugate (ADC) composed of an Fc-silenced, humanized IgG1 monoclonal antibody, a proprietary polysarcosine hydrophobicity masking agent with a dipeptide cleavable linker, and the topoisomerase I inhibitor payload exatecan. It has a drug-antibody ratio (DAR) of 8:1. In preclinical models, LY4170156 has shown activity against a range of FRα-expressing tumors, including low and moderate FRα-expressing ovarian tumors as well as other solid tumors.⁴

Currently, biomarker testing is not necessary to identify eligible patients.

LY4170156 is being studied in ovarian and endometrial cancers, as well as other FRFRα-expressing solid tumors. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

BAF (mSWI/SNF) is a chromatin remodeling complex comprised of multiprotein subunits. BAF requires either SMARCA2 (BRM) or SMARCA4 (BRG1), mutually exclusive ATPase subunits, for chromatin remodeling to occur. Inhibiting SMARCA2 in SMARCA4-deficient cancer is expected to cause synthetic lethality.¹ SMARCA4 mutations are observed in multiple tumor types, including up to 11% in non-small cell lung cancers.²

LY4050784 is a first-in-class, potent, selective, oral SMARCA2 (BRM) inhibitor with greater than 30-fold selectivity for SMARCA2 (BRM) over SMARCA4 (BRG1).³ Preclinical models have demonstrated tumor regression or tumor growth inhibition in SMARCA4-mutant cell lines containing KRAS, TP53, STK11, and KEAP1.³

SMARCA4 mut
SMARCA4 loss

LY4050784 is being studied in clinical trials in patients with non-small cell lung cancer and other solid tumors. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Fibroblast growth factor (FGF) receptor 3 (FGFR3) is a member of the highly conserved FGFR family of transmembrane receptors.^1-3 There are four FGF receptors, FGFR1-4, that each consist of an extracellular ligand-binding domain, transmembrane domain, and an intracellular tyrosine kinase domain.^2,3

Receptor dimerization induced upon binding of the extracellular domain with a high-affinity member of the FGF family of ligands leads to phosphorylation of the intracellular domain and phospholipase Cγ, PI3K-AKT, RAS-MAPK-ERK, and STAT pathways activation, playing a critical role in several biological and developmental processes.^1,3,4

FGFR3 aberrations act as oncogenes across tumor types and have been identified in 15%-20% of advanced urothelial bladder cancers, ~15% of uterine carcinosarcomas, ~5% of endometrial cancers, and less frequently (<5%) in other solid tumor malignancies.^2,3,5,6

Activating FGFR3 alterations are diverse and include point mutations, fusions, amplifications, and overexpression.^1-4

Dysregulation of FGFR3 promotes oncogenesis and tumor cell proliferation, migration, and survival.^1-4,7

LOXO-435 is an isoform-selective FGFR3 inhibitor that has shown antitumor activity across FGFR3-mutant in vivo preclinical models, with preserved potency against FGFR3 gatekeeper resistance mutants.⁶

LOXO-435 spares FGFR1 and FGFR2 in preclinical in vivo models.⁶

Activating FGFR3 alterations include point mutations, fusions, amplifications, and overexpression. FGFR3 is a prognostic and predictive marker in urothelial carcinoma.

LOXO-435 is being investigated in clinical trials in patients with advanced urothelial carcinoma and other solid tumors harboring an FGFR3 alteration. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

LY3410738 is a potent, selective, and covalent inhibitor of mutant IDH1 that has been shown in vitro and in vivo to rapidly inactivate mutant IDH1 and inhibit 2-HG production without impacting wild-type IDH1.⁷

IDH1/2 mutations in are prognostic and predictive in cholangiocarcinoma and in acute myeloid leukemia.

LY3410738 is under investigation in solid tumors harboring an IDH1 R132X mutation, including cholangiosarcoma, chondrosarcoma and glioma. LY3410738 is under investigation in AML patients with an IDH1/2 mutation. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

KRAS is one of the most commonly mutated oncogenes across all tumor types. KRAS G12C represents a KRAS mutation in patients with non-small cell lung cancer (14%), colorectal cancer (3%), and other solid tumors (1%-3%).¹ KRAS G12D represents a KRAS mutation that is identified in patients with pancreatic cancer (37.0%), colorectal cancer (12.5%), and non-small cell lung cancer (4.9%).²

Olomorasib is a selective covalent inhibitor of KRAS G12C; it demonstrates activity as monotherapy and in combination with other anticancer therapies in preclinical models. It has pharmacokinetic properties supporting its advancement into clinical testing. Olomorasib has been shown in vitro to target a KRAS G12C mutation, thereby inhibiting mutant KRAS-dependent signaling.³

LY3962673 is a potent, oral, KRAS G12D inhibitor; in preclinical models, it has demonstrated dose-dependent tumor growth inhibition as monotherapy and in combination.¹ LY3962673 is highly selective against HRAS, NRAS, KRAS, and other non-G12D-mutant KRAS. In a 133-molecule off-target panel screen, there were no off-target activities at biologically meaningful exposures.⁶

KRAS G12C/D mutations are prognostic and predictive in NSCLC and in colorectal adenocarcinoma. KRAS G12D is also prognostic and predictive in pancreatic cancer.

Olomorasib is under investigation in NSCLC, colorectal adenocarcinoma, and in patients with other advanced solid tumors harboring a KRAS G12C mutation.

LY3962673 is under investigation in pancreatic cancer, colorectal adenocarcinoma, NSCLC, and in patients with other advanced solid tumors harboring a KRAS G12D mutation.

For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers and less commonly in other cancers.¹

LOXO-783 is a potent, highly mutant-selective, brain-penetrant, allosteric small molecule PI3Kα H1047R inhibitor.¹

Mutations in PIK3CA, the gene for PI3Kα, may be prognostic and predictive in mBC.

LOXO-783 is under investigation in patients with mBC and other solid tumors with a PI3Kα H1047R mutation. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Rearranged during transfection (RET) fusions have been identified in approximately 2% of non-small cell lung cancer,^1,2 approximately 10% of papillary thyroid cancer,^3,4 and less than 1% in other solid tumors including pancreatic and colorectal cancer.^5-7 RET point mutations account for approximately 60% of medullary thyroid cancer.^8-10 Cancers that harbor activating RET fusions or RET mutations depend primarily on this single constitutively activated kinase for their proliferation and survival. This dependency renders such tumors highly susceptible to small-molecule inhibitors targeting RET.

Selpercatinib is a selective, potent, CNS-active, small-molecule inhibitor of RET. Selpercatinib possesses nanomolar potency against diverse RET alterations, including RET fusions, activating RET point mutations, and acquired resistance mutations. Selpercatinib has been shown in vitro and in vivo to exhibit specificity for RET, with limited activity against other tyrosine kinases.^11,12

RET fusions in solid tumors are predictive of response to selpercatinib, and RET point mutations in MTC are also predictive of benefit from selpercatinib.

Selpercatinib is under investigation in patients with RET fusion-positive NSCLC, non-MTC, and other solid tumors. Selpercatinib is also under investigation in patients with RET-mutant MTC. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Bruton's tyrosine kinase (BTK) is critical for the propagation of B-cell receptor signaling and is upregulated in many B-cell malignancies as compared with normal B cells. BTK inhibition, both in vitro and in vivo, decreases proliferation and survival signals.¹

Pirtobrutinib is an investigational, oral, highly selective (in preclinical studies, over 300-fold more selective for BTK vs 98% of 370 non-BTK-kinases) non-covalent (reversible) BTK inhibitor.^2,3 It possesses nanomolar potency independent of BTK C481 status in enzyme and cell-based assays.^2-4 Pirtobrutinib has been shown in preclinical studies to reversibly bind BTK, have high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and predominantly avoid off-target kinases.²

Pirtobrutinib targets wild-type and mutant BTK, but testing is not necessary to identify eligible patients.

Pirtobrutinib is being investigated in clinical trials in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and non-Hodgkin’s lymphoma. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Many human tumors acquire alterations which can lead to the activation of cyclin-dependent kinases (CDKs). These alterations include mutations that directly activate CDK4/6; gene amplifications, which increase expression of various protein activators such as D-type cyclins; as well as genetic losses, which reduce expression of protein inhibitors such as p16. These various mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions.^1,2

Abemaciclib has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4/6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell-cycle arrest and inhibition of cell proliferation.^3,4

Biomarker testing is not necessary to identify eligible patients.

Abemaciclib is being investigated in clinical trials in patients with early or advanced/metastatic breast cancer. Abemaciclib is also being investigated in clincal trials for pediatric and AYA patients with neuroblastoma or Ewing's sarcoma. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Estrogen signaling plays an important role in organ development and growth. In certain cancers, abnormal estrogen signaling via the estrogen receptor is a component of tumor growth.¹ Disruption of estrogen signaling by selective estrogen receptor degraders (SERDs) is one of the treatment options for patients with estrogen-receptor-positive (ER+) cancers.

Imlunestrant is an orally available SERD that suppresses estrogen signaling and subsequently inhibits cell proliferation in ER-expressing tumor models.^2,3

ESR1 mutations are prognostic in mBC, but biomarker testing is not necessary to identify patients eligible for ER degraders (eg, SERDs).

Imlunestrant is being investigated in clinical trials in patients with early or advanced/metastatic ER+ breast cancer, and in ER+ endometrial cancer. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.

Angiogenesis is a tightly regulated, multiple-step process, which results in the formation of new blood vessels from preexisting vasculature and is an important component in the development and progression of malignant disease. Signaling by vascular endothelial growth factor (VEGF) receptor-2 in endothelial cells plays a role in inducing normal and pathologic angiogenesis and is activated by binding of ligands VEGF-A, VEGF-C, and VEGF-D.^1-3

Ramucirumab is a human IgG1 monoclonal antibody receptor antagonist that has been shown in preclinical studies to bind to and block the activation of VEGF receptor-2 by preventing the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D.^4,5

Biomarker testing is not necessary to identify eligible patients.

Ramucirumab is being investigated in clinical trials in patients with NSCLC. Ramucirumab is also being investigated in clinical trials in pediatric patients with relapsed, recurrent, or refractory tumors. For more information about our clinical trials, visit www.lillyloxooncologypipeline.com or www.clinicaltrials.gov.