ciforadenant (CPI-444) / Ligand, Corvus Pharma, Angel Pharma - LARVOL DELTA

Phase 1b/2 trial of Ipilimumab, Nivolumab, and Ciforadenant (INC) (adenosine A2a receptor antagonist) in first-line advanced renal cell carcinoma (KCRS 2023) - P=1b/2 | N=50 | "The primary objective is to determine the safety and tolerability and to assess the depth of response (>50% by RECIST 1.1 Eisenhaur, 2009) based on a Bayesian design in patients with advanced RCC treated with ipilimumab, nivolumab, and ciforadenant. Secondary objectives will estimate the objective response rate (ORR), duration of response (DOR) progression free survival (PFS), progressive disease (PD) rate, and irAE rate of ipilimumab, nivolumab, and ciforadenant combination in untreated advanced RCC. Exploratory objectives include assessing gene expression signatures and pharmacodynamic parameters with outcome."

Clinical • Metastases • P1/2 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ADORA2A

Phase Ib/II trial of ipilimumab, nivolumab, and ciforadenant (adenosine A2a receptor antagonist) in first-line advanced renal cell carcinoma (RCC), a kidney cancer research consortium study (ESMO 2025) - P1/2 | "RNA signatures including a previously identified exploratory adenosine signature (Fong et al., 2020) did not enrich for response to treatment while the IMmotion 151/OPTIC IO (Motzer et al., 2020) cluster demonstrated significantly higher objective response rates (100% in IO with n=4 vs 30% in Angio cluster with n=21, p=0.032) and correlated with PFS. Conclusions Ciforadenant in combination with ipilimumab and nivolumab in front-line advanced ccRCC showed acceptable safety but failed to improve efficacy."

Clinical • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ADORA2A

Phase 1b/2 trial of Ipilimumab, Nivolumab, and Ciforadenant (INC) (adenosine A2a receptor antagonist) in first-line advanced renal cell carcinoma (KCRS 2022) - "In the same study, the addition of ciforadenant to PD-L1 blockade with atezolizumab was shown to be safe and demonstrate activity with mPFS of 5.8 months and OS probability at 25 months of 90%. Exploratory objectives include assessing gene expression signatures and pharmacodynamic parameters with outcome. Results n/a Conclusions n/a Keywords: adenosine, metabolism, first-line, immunotherapy"

Clinical • IO biomarker • P1/2 data • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ADORA2A • CTLA4 • ENTPD1

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Adenosine pathway as a therapeutic target in diffuse large B cell lymphoma (ASH 2025) - "Shortstimulation with A2AR agonist (CGS-21680) causes an increase in intracellular cAMP in some cell lines(HBL-1, Ly7, Ly1) but not in others (Ly19, Ly10). This increase in cAMP can be reverted with A2ARantagonists (ciforadenant and istradefylline)...Ciforadenant at both doses increased survival in B6but not in NOD-SCID mice, with time of death considered when tumors reached 2 cm and mice wereeuthanized (Log rank (Mantel-Cox) test p=0.019). Taken together our results demonstrate that DLBCLcells are resistant to the inhibitory effects of eADO seen in normal B cells, and that A2AR antagonists areeffective for the treatment DLBCL via an immune mediated mechanism in a preclinical model of DLBCL."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • BCL2 • CD38 • CD73 • ENTPD1 • HLA-C • LY9 • NT5E • SDC1

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2026 ➔ Nov 2025

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Triplet Therapy Proves Feasibility, Lacks Enhanced Efficacy in Advanced ccRCC (Targeted Oncology) - "'In this first kidney cancer research consortium trial, this triplet therapy was feasible and well-tolerated in this early analysis, and the deep response rate and [ORR] was not significantly affected by the addition of ciforadenant,' concluded Beckermann during the presentation."

Audio • Renal Cell Carcinoma

Discovery of Novel Triple A1/A2A/A2B Adenosine Receptor Antagonists for Cancer Immunotherapy. (PubMed, J Med Chem) - "Compound 14a also effectively restored T cell proliferation suppressed by 5'-N-ethylcarboxamidoadenosine (NECA) and exhibited superior T cell-mediated cytotoxicity in coculture systems with A1R- and PD-L1-expressed cancer cells compared with ciforadenant (A2AR antagonist) and etrumadenant (A2AR/A2BR dual antagonist). Moreover, the combination of compound 14a with avelumab, an anti-PD-L1 antibody, resulted in enhanced infiltration of effector T cells and significantly increased the CD8+/Treg ratio in the CT26 syngeneic mouse model, substantially inhibiting tumor growth. Therefore, compound 14a is a promising candidate for multitargeted immunomodulation in cancer immunotherapy."

Journal • Immunology • Oncology • CD8

Corvus Pharmaceuticals Announces Presentation of Interim Data from the Phase 1b/2 Clinical Trial of Ciforadenant for Patients with Metastatic Renal Cell Cancer at the European Society for Medical Oncology (ESMO) Congress 2025 (GlobeNewswire) - "The trial enrolled 50 patients (8 in Phase 1b portion, 42 in Phase 2 portion)....The deep response rate was 34%, demonstrating an improvement compared to historical data for the combination of ipilimumab and nivolumab alone, though not statistically significant at this point in time. 19 patients with stable or responding disease remain on therapy with the potential to achieve deep responses. The ORR by was 46%, including two complete responses and 21 partial responses. The median PFS is 11.04 months."

P1/2 data • Clear Cell Renal Cell Carcinoma

Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (Adenosine A2a Receptor Antagonist) in First-line Advanced Renal Cell Carcinoma. (clinicaltrials.gov) - P1/2 | N=50 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=24 ➔ 50

Enrollment change • Enrollment closed • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

CD73-expressing endometrial regenerative cell-derived exosomes mitigate acute cardiac allograft rejection through regulating adenosine metabolism in mice. (PubMed, Stem Cell Res Ther) - "CD73 expression is crucial for the ability of ERC-exos to generate adenosine to mitigate acute cardiac allograft rejection in mice. ERC-exos combined with rapamycin can prolong allograft survival."

Journal • Preclinical • Cardiovascular • Solid Organ Transplantation • Transplant Rejection • Transplantation • ADORA2A • CD4 • CD73 • NT5E

Synergistic blockade of SHP-2 and A2AR signal pathways with targeted nanoparticles restores anti-tumor immunity of CD8+ T cells. (PubMed, J Control Release) - "SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced cancer immunotherapy."

Journal • Oncology • CD8

Acid-Responsive Disassembly of Nanomedicines for Extracellular Drug Delivery Reversing Glioblastoma Immunosuppressive Microenvironment by Targeting the Adenosine-A2AR Pathway. (PubMed, Small) - "Additionally, the poly-l-histidine core can undergo protonation in the acidic microenvironment, resulting in rapid disintegration of PCNPs and facilitating the quick release of the encapsulated CPI-444 (an extracellular adenosine receptor blocker) and temozolomide, inducing immunogenic cell death and blocking extracellular adenosine receptors to reverse the immunosuppressive feedback signaling pathway of the adenosinergic axis. This combination therapy has shown a novel therapeutic strategy for extracellular immune checkpoint blockade in GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Immunity/metabolism dual-regulation via an acidity-triggered bioorthogonal assembly nanoplatform enhances glioblastoma immunotherapy by targeting CXCL12/CXCR4 and adenosine-A2AR pathways. (PubMed, Biomaterials) - "AMD3100 (CXCR4 antagonist) and CPI-444 (adenosine 2A receptor inhibitor) were formulated into micelles, denoted as AMD@iNPDBCO and CPI@iNPN3, respectively. Furthermore, the nanoplatform remarkably amplifies immuno-radiotherapy by potently evoking cytotoxic CD8+ T cell priming, and synergized with immune checkpoint blockade by delaying CD8+ T cell exhaustion. Our work highlights the potential of the in situ assembly nanoplatform tailored for delivery of extracellular-targeted therapeutic agents for boosting GBM immunotherapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD8 • CXCL12 • CXCR4

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=675 ➔ 314

Enrollment change • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Evolution of myeloid-mediated immunotherapy resistance in prostate cancer. (PubMed, Nature) - "Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy."

IO biomarker • Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ADORA2A • CD8 • SPP1

Corvus Pharmaceuticals Provides Business Update and Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "Corvus is collaborating with the Kidney Cancer Research Consortium in a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1)....The clinical trial is expected to enroll up to 60 patients and as of September 30, 2024, a total of 46 patients were enrolled in the trial....The analysis of the clinical trial continues to meet the threshold for efficacy and therefore enrollment continues. Along with our partners at the Kidney Cancer Research Consortium, we have decided to continue our follow-up of patients on the trial before presenting the data. Therefore, we will not be presenting this data at the GU Malignancy conference taking place in late November and will instead target a presentation sometime in 2025."

P1/2 data • Trial status • Renal Cell Carcinoma

Corvus Pharmaceuticals Announces New Data Highlighting Potential of Ciforadenant to Overcome Immunotherapy Resistance in Metastatic Castration Resistant Prostate Cancer (GlobeNewswire) - "The researchers created a murine model that confirmed that SPP1+ macrophages were associated with suppressed immunity to prostate cancer and shortened overall survival....Ciforadenant treatment associated with reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy in the model. Ciforadenant treatment associated with reduced SPP1+ macrophage infiltration in the tumors, supporting a shift to a less immunosuppressive myeloid environment."

Preclinical • Castration-Resistant Prostate Cancer

Identification and therapeutic target of myeloid-mediated mechanisms of immunotherapy resistance in prostate cancer (PCF 2024) - "Clinical validation demonstrated that mCRPC patients receiving a combination of adenosine receptor inhibition (ciforadenant) and PD-L1 blockade (atezolizumab) exhibited improved anti-tumor efficacy compared to those on monotherapy. Our studies reveal a significant increase in immunosuppressive SPP1 hi-TAM prevalence as prostate cancer progresses to lethal stages. These macrophages play a critical role in resistance to ICIs through adenosine signaling. Our findings highlight the potential of targeting these cells and their signaling pathways as promising therapeutic strategies."

Castration-Resistant Prostate Cancer • Castration-Sensitive Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • SPP1

Corvus Pharmaceuticals Provides Business Update and Reports Second Quarter 2024 Financial Results (GlobeNewswire) - "Corvus is collaborating with the Kidney Cancer Research Consortium in a Phase 1b/2 clinical trial...The clinical trial is expected to enroll up to 60 patients and as of May 31, 2024 a total of 32 patients were enrolled in the trial....As of May 31, 2024, the interim analysis of the clinical trial has met the threshold for efficacy and therefore enrollment continues....Angel Pharmaceuticals, Corvus’ partner in China, is enrolling patients in an expansion cohort of a Phase 1/1b clinical trial of mupadolimab in patients with relapsed non-small cell lung cancer (NSCLC)....Research and development expenses for the three months ended June 30, 2024 totaled $4.1 million compared to $4.0 million for the same period in 2023. The increase of $0.1 million was primarily due to higher clinical trial costs associated with the development of soquelitinib."

Commercial • Enrollment status • Trial status • Genito-urinary Cancer • Hematological Malignancies • Kidney Cancer • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Peripheral T-cell Lymphoma • Renal Cell Carcinoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Extracellular vesicles from seminal plasma interact with T cells in vitro and drive their differentiation into regulatory T-cells. (PubMed, J Extracell Vesicles) - "The adenosine A2A receptor-specific antagonist CPI-444 also reduced effects of spEVs on T-cells, consistent with the notion that the development of Tregs and their immune suppressive functions are under the influence of adenosine-A2A receptor signalling. We found that adenosine is highly enriched in spEVs and propose that spEVs are targeted to and endocytosed by T-cells, after which they may release their adenosine content into the lumen of endosomes, thus allowing endosome-localized A2A receptor signalling in spEVs targeted T-cells. Collectively, these data support the idea that spEVs can prime T cells directly for differentiation into Tregs."

Journal • Preclinical • ADORA2A • CD4 • FOXP3 • IFNG • IL10 • IL2 • IL2RA • IL7R

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=675 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Jun 2026 ➔ Sep 2025 | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2027 ➔ Nov 2026

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Corvus Pharmaceuticals Provides Business Update and Reports Fourth Quarter and Full Year 2023 Financial Results (GlobeNewswire) - "The Kidney Cancer Research Consortium is enrolling a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The Phase 1b portion of this trial has been completed and patients are now being enrolled in the Phase 2 portion. The clinical trial is expected to enroll up to 60 patients and initial data is anticipated in the first half of 2024."

P1/2 data • Trial status • Genito-urinary Cancer • Kidney Cancer • Renal Cell Carcinoma • Solid Tumor

Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (Adenosine A2a Receptor Antagonist) in First-line Advanced Renal Cell Carcinoma. (clinicaltrials.gov) - P1/2 | N=24 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (Adenosine A2a Receptor Antagonist) in First-line Advanced Renal Cell Carcinoma. (clinicaltrials.gov) - P1/2 | N=24 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Recruiting

Enrollment open • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor