quemliclustat (AB680) / Arcus Biosci, Gilead, Otsuka, Takeda - LARVOL DELTA

Adenosine production suppression and PD-1 immune check point inhibitor for treatment of malignant pleural mesothelioma. (MPM) (AACR 2025) - "After three weeks we started monitoring tumor growth and the animals were randomized into five groups of three mice each for treatment with PBS 100 μl (control), Pembro (anti murine PD-1; MCE ) 4.4 mg/Kg, TT-4 (ADORA2 Inhibitor Portage), 3 mg/Kg, Pembro+TT-4, AB-680 (CD73 inhibitor, MCE, HY-125286) 20 mg kg) and Pembro+AB-680 were injected every two days for three weeks. Inhibition of the purinergic pathway exerts a significant immune-mediated MPM growth inhibition"

IO biomarker • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • ADORA2A • ADORA2B • CD73 • CD8 • ENTPD1

The adenosine pathway is an actionable multitarget for mesothelioma (MMe) (ELCC 2025) - "Inhibition of the purinergic pathway exerts significant immune-mediated growth inhibition vs MPM."

IO biomarker • Lung Cancer • Oncology • Solid Tumor • ADORA2B • CD73 • ENTPD1

EDGE-Gastric: A Safety and Efficacy Study of Treatment Combinations With and Without Chemotherapy in Adult Participants With Advanced Upper Gastrointestinal Tract Malignancies (clinicaltrials.gov) - P2 | N=333 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • PD-L1

Arcus Biosciences Reports Fourth-Quarter and Full-Year 2024 Financial Results and Provides a Pipeline Update (Businesswire) - "Pipeline Highlights:...CD73-Adenosine Axis:...(i) Quemliclustat: In the fourth quarter of 2024, Arcus initiated PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in pancreatic cancer. In February 2025, Arcus’s partner, Taiho, dosed their first patient in Japan for PRISM-1; (ii) Etrumadenant: Arcus plans to meet with the FDA in the first half of 2025 to clarify next steps for ARC-9, evaluating etrumadenant plus zimberelimab, FOLFOX, chemotherapy and bevacizumab (EZFB) versus regorafenib in third-line metastatic colorectal cancer (mCRC)."

FDA event • Trial status • Colorectal Cancer • Pancreatic Ductal Adenocarcinoma

Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC) (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: Nataliya Uboha | Trial completion date: Jul 2025 ➔ Jul 2027 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Hepatology • Oncology • Solid Tumor

PRISM-1: Study of Quemliclustat and Chemotherapy Versus Placebo and Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P3 | N=610 | Recruiting | Sponsor: Arcus Biosciences, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

ARC-9: An Open Label Study Evaluating the Efficacy and Safety of Etrumadenant (AB928) Based Treatment Combinations in Participants With Metastatic Colorectal Cancer. (clinicaltrials.gov) - P1/2 | N=227 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Trial completion date: Oct 2024 ➔ Jul 2025 | Trial primary completion date: Oct 2024 ➔ Jul 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

Identification and Analysis of Anticancer Therapeutic Targets from the Polysaccharide Krestin (PSK) and Polysaccharopeptide (PSP) Using Inverse Docking. (PubMed, Molecules) - "This led to the identification interactions and similarities of PSK and the AB680 inhibitor in the active site of CD73. With the isoform of the K-RAS protein, PSK bonded to the TYR32 amino acid at switch 1, while with BAK it bonded to the region of the α1 helix, while PSP bonded to the activation site and the C-terminal and N-terminal ends of that helix. In Bcl-2, PSK interacted at the binding site of the Venetoclax inhibitor, showing similarities with the amino acids ASP111, VAL133, LEU137, MET115, PHE112, and TYR108, while PSP had similarities with THR132, VAL133, LEU137, GLN118, MET115, APS111, PHE112, and PHE104."

Journal • Oncology • BCL2 • CD59 • CD73 • KRAS

CD73-Adenosine Axis: Quemliclustat (small-molecule CD73 inhibitor) and Etrumadenant (A2a/A2b receptor antagonist) (Businesswire) - "Quemliclustat: Arcus has initiated PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in pancreatic cancer....Etrumadenant: Biomarker data from cohort B of ARC-9, a randomized Phase 1b/2 study evaluating etrumadenant plus zimberelimab, FOLFOX chemotherapy and bevacizumab (EZFB) versus regorafenib in third-line metastatic colorectal cancer (mCRC), are being presented at SITC in November."

Biomarker • P1/2 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Quemliclustat (CD73 Inhibitor) reduces adenosine-regulated NR4A gene expression and increases mPDAC inflammation in patients from the ARC-8 trial (AACRPanCa 2024) - P1, P1b/2 | "Quemli, in combination with gemcitabine/nab-paclitaxel (G/nP) ± anti-PD-1 antibody zimberelimab (zim), demonstrated encouraging clinical activity in the first line (1L) mPDAC study ARC-8 (NCT04104672), with median OS ranging from 14.6-19.4 months...Analysis of a published transcriptional dataset from the nivolumab + G/nP control arm of the PRINCE trial in front-line mPDAC (NCT03214250) indicated that high levels of tumor NR4A1, 2, and 3 expression portend significantly worse clinical outcomes in patients treated with this IO/chemotherapy regimen, highlighting a potential opportunity for quemli to provide clinical benefit by reversing adenosine-mediated immunosuppression in mPDAC...Quemli + G/nP treatment was associated with a reduction in tumor expression levels of adenosine-regulated NR4A gene family and was accompanied by an increase in tumor inflammation. Given the adenosine-modulating MoA, patients with mPDACs expressing high levels of NR4A in..."

Clinical • IO biomarker • Gastrointestinal Cancer • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD73 • NR4A1 • NR4A2 • NR4A3

ARC-6: Adenosine Receptor Antagonist Combination Therapy for Metastatic Castrate Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=173 | Completed | Sponsor: Arcus Biosciences, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

The first small molecule CD73 inhibitor entered Phase III stage [Google translation] (bydrug.pharmcube.com) - "On September 23, the United States clinical trial website clinicaltrials showed that the small molecule CD73 inhibitor Quemliclustat (AB680) started phase III clinical trial (PRISM-1), becoming the first small molecule CD73 inhibitor to enter the phase III stage...The study is a multicenter, randomized, double-blind, placebo-controlled clinical trial (n=610) to evaluate the efficacy and safety of Quemliclustat in combination with chemotherapy (nab-paclitaxel + gemcitabine) versus placebo plus chemotherapy in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The primary endpoint of the study was overall survival (OS)."

Trial status • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Zimberelimab and Quemliclustat in Combination with Chemotherapy for the Treatment of Patients with Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Jonsson Comprehensive Cancer Center | Suspended ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

PRISM-1: Study of Quemliclustat and Chemotherapy Versus Placebo and Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P3 | N=610 | Not yet recruiting | Sponsor: Arcus Biosciences, Inc.

New P3 trial • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

EDGE-Lung: Study With Immunotherapy Combinations in Participants With Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=320 | Recruiting | Sponsor: Gilead Sciences | Trial completion date: Sep 2026 ➔ Dec 2027 | Trial primary completion date: Sep 2026 ➔ Dec 2027

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Arcus Biosciences Reports Second-Quarter 2024 Financial Results and Provides a Pipeline Update (Businesswire) - "Pipeline Highlights:...(i) Etrumadenant: Biomarker data from...ARC-9...study are expected to be presented at a scientific conference in the second half of 2024;...(ii) Quemliclustat: Initiation of a Phase 3 trial, PRISM-1, of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in pancreatic cancer is expected to begin by early 2025;...(iii) Early Clinical Programs: Dose escalation for AB801, a potent and highly selective small-molecule AXL inhibitor, continues. Arcus anticipates advancing this molecule into expansion cohorts in NSCLC in early 2025."

Biomarker • New P3 trial • P1/2 data • Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer

Preventive Treatment with a CD73 Small Molecule Inhibitor Enhances Immune Surveillance in K-Ras Mutant Pancreatic Intraepithelial Neoplasia. (PubMed, Cancer Prev Res (Phila)) - "To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse (GEM) model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression...The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pancreatitis • Solid Tumor • CD4 • CD73 • CD8 • KRAS • NT5E

ARC-9: An Open Label Study Evaluating the Efficacy and Safety of Etrumadenant (AB928) Based Treatment Combinations in Participants With Metastatic Colorectal Cancer. (clinicaltrials.gov) - P1/2 | N=227 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Trial completion date: Jul 2024 ➔ Oct 2024 | Trial primary completion date: Jul 2024 ➔ Oct 2024

Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy. (PubMed, Adv Mater) - "Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge,..."

Immunogenic cell death • Journal • Oncology • CD73

Targeting CD73 limits tumor progression and enhances anti-tumor activity of anti-PD-1 therapy in intrahepatic cholangiocarcinoma. (PubMed, J Cancer Res Clin Oncol) - "CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response."

IO biomarker • Journal • Biliary Cancer • Cholangiocarcinoma • CNS Disorders • Depression • Gastrointestinal Cancer • Oncology • Psychiatry • Solid Tumor • CD4 • CD73 • CD8 • GZMB • ICOS • NICD • NT5E • TNFA

Taiho Pharmaceutical Exercises Option for an Exclusive License to Quemliclustat in Japan and Certain Territories in Asia (Businesswire) - "Arcus Biosciences, Inc...and Taiho Pharmaceutical Co., Ltd...today announced that Taiho exercised its option for quemliclustat...an investigational small molecule CD73 inhibitor, in Japan and certain other territories in Asia (excluding mainland China). This option exercise is based on an option and license agreement between Taiho and Arcus contracted in September 2017. This is the fourth option exercise by Taiho to an Arcus program....In exchange for the exclusive license of quemliclustat, Taiho will make an option exercise payment, as well as additional payments upon achievement of clinical, regulatory and commercialization milestones, and, if any products from the program are approved, will pay royalties on net sales of such products.... In 2024, Arcus plans to initiate the global, registrational Phase 3 study PRISM-1, comparing quemliclustat plus chemotherapy to chemotherapy alone as a treatment for patients with previously untreated metastatic pancreatic ductal..."

Licensing / partnership • Pancreatic Ductal Adenocarcinoma

QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564. (ASCO 2024) - P2 | "Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC."

Clinical • IO biomarker • Metastases • P2 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD73 • NT5E • PD-L1

ARC-8: A Study to Evaluate the Safety and Tolerability of AB680 in Participants With Gastrointestinal Malignancies (clinicaltrials.gov) - P1 | N=195 | Recruiting | Sponsor: Arcus Biosciences, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

SBRT-AMICO: Adenosine Signaling Modulation and Immune Checkpoint Inhibition With Hormone Sensitive Oligometastatic Prostate Cancer (clinicaltrials.gov) - P2 | N=23 | Recruiting | Sponsor: Catherine Spina | Trial primary completion date: Apr 2024 ➔ Dec 2025

Checkpoint inhibition • Metastases • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

CBO421: A novel drug Fc-conjugate to prevent tumor immune evasion via the CD73/adenosine pathway (AACR 2024) - "In vivo efficacy of CBO421 monotherapy was evaluated in a syngeneic mouse model.Results CBO421 exhibited a binding affinity to human CD73 (KD = 0.8 nM) that was comparable to or greater to the affinity observed with small molecule inhibitors (AB680, OP-5244) and CD73-targeting mAbs (oleclumab, mupadolimab biosimilars). CBO421 demonstrated high potency in functional cell-based assays and robust antitumor efficacy in a syngeneic mouse model. Currently, CBO421 is being advanced as a clinical development candidate for the treatment of solid cancers."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD73 • CD8 • NT5E