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

CD73 Serves as a Prognostic Biomarker and Therapeutic Target in Combination With Lorlatinib for ALK-Positive NSCLC (IASLC-WCLC 2026) - "A tumor-T cell co-culture system was used to evaluate the therapeutic efficacy of ALK-TKI Lorlatinib in combination with CD73 inhibitor Oleclumab or adenosine A2A receptor antagonist CPI-444. The ALK-CD73-adenosine axis drives immune suppression and tumor progression. ALK-TKI combined with CD73 inhibitor or adenosine A2A receptor inhibitors exerts significant immune-activating effects, offering a novel therapeutic strategy for ALK -positive NSCLC."

Biomarker • Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ADORA2A • ALK • CD73 • CD8 • IFNG • NT5E • TNFA

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

GSH-responsive nanoparticle drug delivery system for simultaneous blockade of CD73/A2AR to reverse adenosine-mediated immunosuppression. (PubMed, Biomater Adv) - "This study designed and synthesized two novel conjugates, BSC and BSPC, which chemically link the CD73 inhibitor betulinic acid (BA) and the A2AR antagonist CPI-444 via a disulfide bond...Furthermore, combination therapy with BSC NPs and an anti-PD-L1 antibody demonstrated a synergistic effect, markedly enhancing the antitumor immune response without inducing significant systemic toxicity. This study provides a novel nano-based combination therapy strategy for reversing adenosine-mediated immunosuppression."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD73

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

TKI Resistance is Associated with Immune Dysfunction in ccRCC (KCRS 2026) - "Likewise, inhibiting A2AR signaling with CPI-444 diminished the expression of tumor-promoting factors and further strengthened the therapeutic efficacy of axitinib in our model system. Conclusions These results show that sunitinib treatment induces an immunosuppressive tumor microenvironment driven by macrophage reprogramming and altered spatial organization. Targeting these macrophage subsets markedly enhances the therapeutic efficacy of TKIs. Keywords RCC, TKI Resistance, Spatial Transcriptomic Profiling, Immune Dysfunction, Macrophage DOD CDMRP Funding yes"

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Renal Cell Carcinoma • Solid Tumor • CAFs • CSF1R • DUX4 • ENTPD1 • IFNG • IL13 • IL4 • PD-L1 • PD-L2

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 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; Study was closed early as the sponsor decided not to continue development of certain treatment combinations.

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

CPI-006 Alone and in Combination With Ciforadenant and With Pembrolizumab for Patients With Advanced Cancers (clinicaltrials.gov) - P1 | N=378 | Recruiting | Sponsor: Corvus Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Mar 2022 ➔ Dec 2023

Combination therapy • Trial completion date • Trial primary completion date • Bladder Cancer • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hepatology • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • MSI

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=250 | Recruiting | Sponsor: Hoffmann-La Roche | N=410 ➔ 250

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

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

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

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=410 | Recruiting | Sponsor: Hoffmann-La Roche | N=292 ➔ 410

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

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=307 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

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

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=435 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Feb 2024 ➔ Nov 2023

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

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=380 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Apr 2022 ➔ Nov 2023

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

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

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=470 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2025 ➔ Nov 2026 | Trial primary completion date: Apr 2024 ➔ Aug 2025

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

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 | Recruiting | Sponsor: Hoffmann-La Roche | N=470 ➔ 675 | Trial completion date: Nov 2026 ➔ Sep 2027 | Trial primary completion date: Aug 2025 ➔ Jun 2026

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

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

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=435 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2023 ➔ Feb 2024 | Trial primary completion date: Feb 2022 ➔ Jun 2022

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

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=435 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2023 ➔ Aug 2025 | Trial primary completion date: Feb 2022 ➔ Apr 2024

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

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=307 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P1/2 trial • Non Small Cell Lung Cancer • PD-L1

Spatial single-cell transcriptomics reveal targetable macrophage subsets associated with antiangiogenic therapy resistance in renal cell carcinoma* (AACR-Kidney 2026) - "Notably, both IFN- and Prolif-TAMs expressed the A2A adenosine receptor (A2AR), and we found that the A2AR antagonist CPI-444 further potentiated the therapeutic response to axitinib treatment.These results show that sunitinib treatment induces an immunosuppressive tumor microenvironment driven by macrophage reprogramming and altered spatial organization. These results show that sunitinib treatment induces an immunosuppressive tumor microenvironment driven by macrophage reprogramming and altered spatial organization. Targeting these macrophage subsets markedly enhances the therapeutic efficacy of TKIs. Disclosure: AI assistance (ChatGPT) was used to polish the wording of this abstract."

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CSF1R • IFNG • PD-L1 • PD-L2

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

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