utomilumab (PF-05082566) / Pfizer, Novartis - LARVOL DELTA

AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) (SABCS 2023) - P2 | " Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1...All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan... This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC."

Clinical • IO biomarker • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • PD-L1

Phase I/II study to evaluate the safety and tolerability of avelumab in combination with other anti-cancer therapies in patients with advanced malignancies (SITC 2023) - P1/2 | "1 Preclinical studies suggest that combining utomilumab (4–1BB agonist) and ivuxolimab (OX40 agonist) with avelumab (an anti-PD-L1 monoclonal antibody) can potentially synergize to enhance T cell function and simultaneously overcome the effects of upregulation of PD-L1 resulting in clinical benefit. Conclusions Combining immune checkpoint inhibitors with checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies. The findings from this study can provide insights for future investigations in this field of research."

Clinical • Combination therapy • Metastases • P1/2 data • Colon Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Adrienne G. Waks | Trial completion date: May 2026 ➔ May 2027

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PD-L1

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=77 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

Development of in vitro models to study CD137 agonist antibody mediated hepatotoxicity (IMMUNOLOGY 2026) - "This fully human in vitro model is a sensitive tool for evaluating immune mediated hepatotoxicity risk for immunostimulatory biotherapeutics."

Late-breaking abstract • Preclinical • Hepatology • CASP3 • CASP7 • GZMB • IFNG • TNFA

AM109, a PSMA×CD137 bispecific antibody with target-dependent T cell activation and potent anti-tumor activity in prostate cancer (AACR 2026) - "In vivo efficacy was evaluated using human CD137 transgenic mice bearing hPSMA/MC38 tumors, where AM109 achieved complete tumor regression at doses of 0.1-0.3 mpk, exhibiting superior potency compared with the reference CD137 agonist utomilumab. Collectively, these findings demonstrate that AM109 selectively activates T cells within the tumor microenvironment, eliciting potent and PSMA-dependent anti-tumor responses with an improved therapeutic window. AM109 therefore represents a promising next-generation immunotherapeutic candidate for the treatment of mCRPC."

Bispecific • IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • FOLH1 • GZMB • IFNG • TNFRSF9

InCITe: Avelumab With Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=145 | Active, not recruiting | Sponsor: Laura Huppert, MD, BA | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Jan 2027 | Trial primary completion date: Jun 2026 ➔ Jan 2027

Enrollment closed • Trial completion date • Trial primary completion date • Tumor mutational burden • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

A novel anti-4-1BB antibody with no liver toxicity and its application in a bi-specific antibody (AACR 2024) - "However, the development of 4-1BB agonist antibodies has encountered challenges, with limited clinical efficacy (e.g., utomilumab) or dose-dependent liver toxicity (e.g., urelumab)...Furthermore, we've developed HLX34, a Her2x4-1BB bispecific antibody, derived from Trastuzumab and HLX25...These results provide evidence that our novel anti-4-1BB antibody activates proper 4-1BB signaling through tumor-enriched FcgRIIB or tumor-associated antigen-mediated clustering, inhibiting tumor growth with good safety in both in vitro and in vivo settings. This underscores HLX34 as a promising alternative therapeutic strategy for next-generation cancer immunotherapy."

Bispecific • Oncology • CD8 • HER-2 • TNFA • TNFRSF9

Multabodies: A next-generation approach for cancer immunotherapy and 4-1BB agonist therapy (AACR 2025) - "However clinical development has been hindered by severe liver toxicity (i.e., urelumab), or insufficient single agent activity, as seen with utomilumab. Furthermore, RBT101 also provided long-term protection in a tumor rechallenge study, suggesting generation of a durable immunological memory response driven by RBT101. These data suggest the Multabody™ platform provides a novel approach to delivering a 4-1BB therapeutic with a differentiated profile to address an unmet clinical need in cancer immunotherapy for patients with solid malignancies."

Oncology • Solid Tumor • TNFRSF9

Agonistic CD137 (4-1BB) anchored immunotherapy (ANK-203) elicits potent 4-1BBL signaling in vitro and therapeutic responses against established tumors without systemic toxicity in vivo* (AACR-IO 2026) - "CD137 agonistic monoclonal antibodies (mAbs) demonstrated preclinical anti-tumor activity, but clinical trials with first-generation CD137 mAbs were limited by dose-dependent hepatotoxicity (urelumab) or lack of efficacy (utomilumab). ANK-203 is the first anchored immunotherapy using a fully humanized CD137 mAb. ANK-203 was associated with enhanced CD137 signaling in vitro and generated significant therapeutic activity in a bilateral MC38 tumor model without signs of systemic toxicity. Further studies to elucidate the impact on immune responses are in progress and ANK-203 may warrant further development for clinical investigation."

IO biomarker • Preclinical • Oncology • CD4 • CD8 • FAM20C • TNFRSF9

Expanding the horizons of cancer therapy with next-generation 4-1BB agonists: a review of molecular and clinical strategies to maximize efficacy and ensure safety. (PubMed, MAbs) - "Driven by the substantial limitations of first generation 4-1BB agonists urelumab and utomilumab, the field has shifted toward engineering next-generation molecules with improved therapeutic windows. Furthermore, we discuss strong rationale for combination strategies, emphasizing how 4-1BB signaling provides the crucial costimulatory signal necessary to sustain durable anti-tumor responses. In summary, this review elucidates the scientific basis of antibody engineering aimed at improving safety and tumor-selective activation of 4-1BB agonists and outlines future directions for optimizing their clinical application in cancer immunotherapy."

Journal • Review • Oncology

Tumor microenvironment changes after treatment with avelumab and immune- stimulating agent combinations in patients with advanced solid tumors. (PubMed, Res Sq) - P1/2 | "Methods We performed whole exome sequencing (WES), bulk RNAseq, multiplex immunofluorescence (mIF) and chromogenic immunohistochemistry (IHC) on tumor tissue and flow cytometry of the peripheral blood to study longitudinal changes following the combination of avelumab with utomilumab (a 4-1BB agonist) (arm A), PF-04518600 (an OX40 agonist) (arm B), utomilumab and PF-04518600 (arm C) and utomilumab and radiotherapy (arm D) in phase I/II study (NCT03217747). Conclusions Our findings, though limited, highlight genomic differences between histologic subsets and outcome as well as the need for combination strategies that drive the recruitment and/or priming of anti-tumor T cells and address low immune permissive tumor states in patients with advanced solid tumors. Clinical trial registration: This clinical trial was registered on clinicaltrials.gov NCT03217747."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CCNE1 • IFNG • KRAS • PIK3CA • TMB • TTN

Utomilumab, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2026 ➔ Dec 2025 | Trial primary completion date: Dec 2026 ➔ Dec 2025 | Active, not recruiting ➔ Completed

Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor • MSI

Development of a nanoparticle-based immunotherapy targeting CD137 for nasopharyngeal carcinoma treatment. (PubMed, Theranostics) - "Urelumab and utomilumab, are two agonistic anti-CD137 antibodies that are most advanced in clinical trials but suffer from liver toxicity and low potency, respectively. In contrast to ure-MSNs, rhCD137-MSN treatment did not induce liver damage, thereby demonstrating a more favorable safety profile than ure-MSNs. This study identifies a formulation of rhCD137L on MSNs that combines high potency with excellent safety."

IO biomarker • Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • CD8 • TNFRSF9

Cardiac Glycosides Induce Immunogenic Changes in Myeloma Cells and Enhance the Efficacy of Monoclonal and Bispecific Antibody Therapy (ASH 2024) - P1 | "Therefore, the 4-1BB agonist Utomilumab is being tested in combination with CAR-T therapy (NCT 03704298).Here, to develop improved immune cell therapies for MM, we evaluated whether CGs enhances the anti-myeloma activity of monoclonal and bispecific antibodies by augmenting immune responses.Methods : Alterations of ICAM1 and 4-1BBL or SLAMF7 at the protein level were evaluated on two MM cell lines, AMO1 and KMS12PE, by flow cytometry after exposure to the CGs, i.e., digoxin, periplocin, ouabain, or hellebrin at minimally toxic concentrations.Treated MM cells were then co-cultured with immune effector cells from healthy donors together with elotuzumab (anti-SLAMF7 antibody) or teclistamab (BCMA bispecific antibody) in the presence or absence of low doses of CGs for 48 h. Thereafter, cytotoxic effects and effector cell activity were evaluated. Digoxin, a drug that can be used in clinical practice, also caused immunogenic changes in MM cells and enhanced the efficacy..."

Clinical • IO biomarker • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Multiple Myeloma • Oncology • ICAM1 • IL2RA • SLAMF7

Tumor microenvironment changes after treatment with avelumab combinations in patients with advanced solid tumors (SITC 2025) - P1/2 | "The impact of using novel therapeutic combinations of checkpoint blockade (avelumab) with immune stimulating agonists such as anti-OX40 and/or anti-4-1BB on the tumor microenvironment and modulation of the immune response is an intriguing strategy to evaluate how these agents interact and whether the hypothetical rationale for combinations can be translated into augmentation of anti-tumor immunity in solid tumors.Methods We performed whole exome sequencing (WES), bulk RNAseq, multiplex immunofluorescence (mIF) and chromogenic assay immunohistochemistry (IHC) on tumor tissue and flow cytometry of the peripheral blood to study changes between post and pre-treatment longitudinal changes following the combination of avelumab with utomilumab (a 4-1BB agonist) (arm A), PF-04518600 (an OX40 agonist) (arm B), utomilumab and PF-04518600 (arm C) and utomilumab and radiotherapy (arm D) in phase I/II study (NCT03217747). Mutations in TP53, TTN and KRAS (mostly p.G12C, p.G12D)..."

Biomarker • Clinical • IO biomarker • Metastases • Tumor microenvironment • Tumor mutational burden • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CCNE1 • IFNG • KRAS • PIK3CA • TMB • TTN

NCI-2018-01118: Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, and Radiation Therapy in Treating Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=173 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Sep 2025 ➔ Apr 2026

Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Oncology • Prostate Cancer • Solid Tumor

The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Adrienne G. Waks | Trial completion date: May 2025 ➔ May 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PD-L1

InCITe: Avelumab With Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Laura Huppert, MD, BA | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: City of Hope Medical Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jun 2024 | Trial primary completion date: Dec 2024 ➔ Jun 2024

Trial completion • Trial completion date • Trial primary completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • CD20

A phase I/II trial of avelumab combinations with ivuxolimab, utomilumab, and radiation therapy in patients with advanced gastrointestinal malignancies. (PubMed, Oncologist) - P1/2 | "Combining avelumab with co-stimulatory checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies (ClinicalTrials.gov Identifier: NCT03217747)."

Journal • P1/2 data • Colon Cancer • Fatigue • Gastric Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Oncology • Pancreatic Cancer • Solid Tumor

Rituximab + Immunotherapy in Follicular Lymphoma (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: Dana-Farber Cancer Institute | Phase classification: P1b ➔ P1 | Active, not recruiting ➔ Terminated; Stopped was stopped prematurely due to drug manufacturer withdrawing supply/funding. Patients already enrolled on study were allowed to continue treatment.

Phase classification • Trial termination • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

NCI-2018-01118: Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, and Radiation Therapy in Treating Patients with Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=173 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8

A Study Of Avelumab In Combination With Other Cancer Immunotherapies In Advanced Malignancies (JAVELIN Medley) (clinicaltrials.gov) - P1/2 | N=409 | Terminated | Sponsor: Pfizer | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Bladder Cancer • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ALK • EGFR • ROS1

ZUMA-11: Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P1 | N=15 | Terminated | Sponsor: Kite, A Gilead Company | Phase classification: P1/2 ➔ P1

Combination therapy • Phase classification • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6