taminadenant (NIR178) / Novartis, Palobiofarma, Xoma - LARVOL DELTA

Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy. (PubMed, Proc Natl Acad Sci U S A) - "However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy."

Journal • Oncology • ADORA2A

Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma. (PubMed, Cancer Lett) - "Furthermore, overexpression of PNP or using taminadenant, a A2aR-targeting inhibitor used in clinical trials, significantly enhances the EGFR-targeted therapeutic response in vitro, as well as in patient-derived organoids, cell-derived xenografts and mouse models bearing human EGFR-driven spontaneous lung tumor. Overall, our findings clarify the role of inosine metabolism in TKI resistance, highlighting a potential therapeutic strategy-targeting the inosine/A2aR axis-to counteract EGFR-TKI tolerance in LUAD treatment."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ADORA2A

CDFF332A12101: DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2025 ➔ Mar 2026 | Trial primary completion date: Sep 2025 ➔ Mar 2026

IO biomarker • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

CDFF332A12101: DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2025 ➔ Sep 2025 | Trial primary completion date: Feb 2025 ➔ Sep 2025

IO biomarker • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jul 2025 ➔ Feb 2025 | Trial primary completion date: Jul 2025 ➔ Feb 2025

Combination therapy • Immuno-oncology • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=180 ➔ 40

Combination therapy • Enrollment change • Enrollment closed • Immuno-oncology • IO biomarker • Metastases • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

KAZ954 Alone and With PDR001, NZV930 and NIR178 in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=77 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons

Combination therapy • IO biomarker • Metastases • Trial termination • Oncology • Solid Tumor • PD-L1

KAZ954 Alone and With PDR001, NZV930 and NIR178 in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=77 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=145 ➔ 77

Combination therapy • Enrollment change • Enrollment closed • IO biomarker • Metastases • Oncology • Solid Tumor • PD-L1

A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies. (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Combination therapy • Metastases • P1 data • Gastrointestinal Cancer • Oncology

KAZ954 Alone and With PDR001, NZV930 and NIR178 in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=145 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2025 ➔ Sep 2023 | Trial primary completion date: Feb 2025 ➔ Sep 2023

Combination therapy • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • PD-L1

KAZ954 Alone and With PDR001, NZV930 and NIR178 in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=145 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2024 ➔ Feb 2025 | Trial primary completion date: Aug 2024 ➔ Feb 2025

Combination therapy • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • PD-L1

Early Adverse Event Derived Biomarkers in Predicting Clinical Outcomes in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy. (PubMed, Cancers (Basel)) - "The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine."

Adverse events • Biomarker • Clinical data • IO biomarker • Journal • Metastases • Endocrine Disorders • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma (clinicaltrials.gov) - P2 | N=317 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Sponsor decision

Combination therapy • Metastases • Trial termination • Breast Cancer • Colon Cancer • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hepatology • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • BRAF • CD8 • EGFR

Phase I/II Study of the A2AR Antagonist NIR178 (PBF-509), an Oral Immunotherapy, in Patients (pts) with Advanced NSCLC (IASLC-WCLC 2018) - P1/2; "NIR178 was well tolerated; AEs were manageable and there were no Gr 4 drug-related AEs. Immune-related AEs may indicate immune stimulation. Clinical benefit was observed in immunotherapy-exposed and -naïve pts irrespective of PD-L1 status. "

Clinical • P1/2 data • PD(L)-1 Biomarker • Non Small Cell Lung Cancer

Phase I/II study of the A2AR antagonist NIR178 (PBF-509) combined with the anti-PD-1 monoclonal antibody spartalizumab in patients with advanced NSCLC (EORTC-NCI-AACR 2018) - P1/2; "NIR178 in combination with spartalizumab was well tolerated; AEs were manageable and there were no Gr 4 treatment-related AEs. The MTD was determined as NIR178 240 mg BID + spartalizumab 400 mg Q4W. Clinical benefit was observed in immunotherapy-exposed and -nave pts."

Clinical • IO biomarker • P1/2 data • PD(L)-1 Biomarker • Non Small Cell Lung Cancer

Phase II study of taminadenant (A2AR antagonist) + spartalizumab (anti PD-1 antibody) in patients with triple negative breast cancer (TNBC) (ESMO-IO 2022) - P2 | "Conclusions TAM + spartalizumab showed clinical benefit in a fraction of pts with relapsed TNBC. Biomarker data support the role of TAM in shifting the immune microenvironment toward a "T-cell–inflamed" tumor, and possibly in increasing the efficacy of anti–PD-1 agents."

Clinical • IO biomarker • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8

Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC). (clinicaltrials.gov) - P1 | N=64 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; This was a sponsor decision and was not a consequence of any safety concern

IO biomarker • Trial termination • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • ER • HER-2 • LAG3 • PD-L1 • PGR

Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC). (clinicaltrials.gov) - P1 | N=64 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2022 ➔ Feb 2023 | Trial primary completion date: Oct 2022 ➔ Feb 2023

IO biomarker • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • ER • HER-2 • LAG3 • PD-L1 • PGR

A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies (AACR 2022) - P1 | "NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties."

Clinical • Combination therapy • IO biomarker • P1 data • Gastrointestinal Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer • NT5E

[VIRTUAL] Phase (Ph) II study of taminadenant (NIR178) + spartalizumab (PDR001) in patients (pts) with microsatellite stable (MSS) colorectal cancer (CRC) (ESMO 2021) - P2 | "Efficacy of taminadenant + spartalizumab showed 5 pts obtained clinical benefit (1 PR and 4 sustained SD with tumor shrinkage), with no difference in response between RAS-WT and RAS-Mt. Taminadenant + spartalizumab was well tolerated in pts with MSS CRC."

Clinical • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ADORA2A

A Phase I/Ib Study of NZV930 Alone and in Combination With PDR001 and /or NIR178 in Patients With Advanced Malignancies. (clinicaltrials.gov) - P1 | N=127 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; After review of data which showed low likelihood of efficacy in these patients Novartis decided to terminate the trial early. Termination was not safety related

Combination therapy • Trial termination • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1; N=180; Recruiting; Sponsor: Novartis Pharmaceuticals; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • IO biomarker • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

A Phase I/Ib Study of NZV930 Alone and in Combination With PDR001 and /or NIR178 in Patients With Advanced Malignancies. (clinicaltrials.gov) - P1 | N=127 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=344 ➔ 127 | Trial completion date: Mar 2023 ➔ Sep 2022 | Trial primary completion date: Mar 2023 ➔ Sep 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC). (clinicaltrials.gov) - P1 | N=64 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jun 2022 ➔ Oct 2022 | Trial primary completion date: Jun 2022 ➔ Oct 2022

IO biomarker • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • ER • HER-2 • LAG3 • PD-L1 • PGR

A Phase I/Ib Study of NZV930 Alone and in Combination With PDR001 and /or NIR178 in Patients With Advanced Malignancies. (clinicaltrials.gov) - P1 | N=344 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Sep 2022 ➔ Mar 2023

Combination therapy • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer