ivuxolimab (PF-04518600) / Pfizer - LARVOL DELTA

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

Advancing In Vivo Detection of T-Cell Function: Development and Preclinical Evaluation of 89Zr-Ivuxolimab, a Human OX40 PET Tracer. (PubMed, J Nucl Med) - " Deferoxamine conjugation and 89Zr radiolabeling were optimized for ivuxolimab. 89Zr-ivuxolimab is a promising radiotracer for clinical translation as an imaging agent for activated T cells. Further investigation of its ability to monitor and predict response to different cancer immunotherapy modalities is warranted."

IO biomarker • Journal • Preclinical • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Oncology • TNFRSF4

Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer (clinicaltrials.gov) - P2 | N=62 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Jul 2026 ➔ Dec 2026 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • 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

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

Phase II randomized double-blind trial of axitinib (Axi) +/- PF 04518600, an OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in metastatic renal cell carcinoma (mRCC): Final analysis (ESMO 2024) - P2 | "In IO-pretreated mRCC pts, Axi + PFOX did not improve PFS compared to Axi alone."

Clinical • Metastases • P2 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • TNFRSF4

Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer (clinicaltrials.gov) - P2 | N=62 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Jul 2024 ➔ Jul 2025

Checkpoint inhibition • Combination therapy • Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PD-L1

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

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=61 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=262 ➔ 61 | Trial completion date: May 2025 ➔ Sep 2026 | Trial primary completion date: May 2025 ➔ Sep 2026

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

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=262 | Recruiting | Sponsor: Pfizer | Trial completion date: Dec 2025 ➔ May 2025 | Trial primary completion date: Dec 2025 ➔ May 2025

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

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: Hope Rugo, MD | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Metastases • 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

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

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies. (PubMed, Cancer) - "The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted."

Journal • Metastases • P1/2 data • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma. (PubMed, Ann Hematol) - P1b | "We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503)."

Combination therapy • Journal • P1 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • TIGIT

BAT6026, a novel anti-OX40 antibody with enhanced antibody dependent cellular cytotoxicity effect for cancer immunotherapy. (PubMed, Front Oncol) - "Several OX40 agonistic antibodies are in the clinical stage for cancer treatment, among which PF-04518600 is the leader and currently in phase II trial. Preclinical safety assessment in non-human primates demonstrated a good safety profile for BAT6026. Together these data warrant further development of BAT6026 into clinical trials for patients with cancer."

Journal • Oncology • CD8 • IL2

Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer (clinicaltrials.gov) - P2 | N=62 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Jul 2024 ➔ Jul 2025 | Trial primary completion date: Jul 2023 ➔ Jul 2024

Checkpoint inhibition • Combination therapy • Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PD-L1

InCITe: Avelumab With Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Patients With Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Hope Rugo, MD | Trial completion date: Jul 2023 ➔ Jun 2024 | Trial primary completion date: Jul 2023 ➔ Jun 2024

Metastases • 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

OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=50 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | N=138 ➔ 50

Enrollment change • Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2

A multi-arm phase Ib/II study designed for rapid, parallel evaluation of novel immunotherapy combinations in relapsed/refractory acute myeloid leukemia. (PubMed, Leuk Lymphoma) - P1/2 | "Overall, 50 patients were enrolled into one of 6 arms: (A) single agent PF-04518600 (OX40 agonist monoclonal antibody), (B) azacitidine + venetoclax + gemtuzumab ozogamicin (GO), (C) azacitidine + avelumab (anti-PD-L1 monoclonal antibody) + GO, (D) azacitidine + venetoclax + avelumab, (E) azacitidine + avelumab + PF-04518600, and (F) glasdegib + GO. This study shows the feasibility of a conducting a multi-arm trial to efficiently and simultaneously evaluate novel therapies in AML, a needed strategy in light of the plethora of emerging therapies. This trial was registered at www.clinicaltrials.gov as NCT03390296."

Journal • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Study Of Avelumab In Combination With Other Cancer Immunotherapies In Advanced Malignancies (JAVELIN Medley) (clinicaltrials.gov) - P1b/2 | N=405 | Terminated | Sponsor: Pfizer | Active, not recruiting ➔ Terminated; The study was terminated since there was no need for further safety or efficacy data to be collected. The participants having benefit from the Investigational treatments have been moved to a continuation study (NCT05059522)

Trial termination • 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 • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ALK • CD8 • EGFR • ROS1

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=262 | Recruiting | Sponsor: Pfizer | Trial completion date: Nov 2024 ➔ Dec 2025 | Trial primary completion date: Nov 2024 ➔ Dec 2025

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

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 2023 ➔ Sep 2024 | Trial primary completion date: Sep 2022 ➔ Sep 2024

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