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

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

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

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

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