pegenzileukin (SAR444245) / Sanofi, Innovent Biologics - LARVOL DELTA

Enhanced therapeutic potential of NK cell-based combination therapies in preclinical cancer models (SITC 2025) - "The study also explored the potential of pegenzileukin, a PEGylated non-alpha rhIL-2 variant engineered for preferential binding to IL-2 βγ receptors...The study provides compelling evidence for improved antitumor activity and NK cell persistence when combined with monoclonal antibodies and cytokine therapy. These results establish a strong foundation for further clinical development of NK cell-based combination immunotherapies in oncology."

Combination therapy • Preclinical • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • IL15 • IL2 • IL21

HAMMER: A Study Evaluating Safety and Therapeutic Activity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors (THOR-707-101) (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Synthorx, Inc, a Sanofi company | Trial completion date: Jun 2026 ➔ Nov 2025 | Trial primary completion date: Jun 2026 ➔ Nov 2025

Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • KRAS

SAR-444245, an engineered not-alpha IL-2 leveraging synthetic biology, modulates critical components of the immune system for durable anti-tumoral activity. (PubMed, J Immunol) - "Overall, we demonstrate that the IL-2 not-alpha agent SAR'245 induces immune responses that promote infiltration of CD8+ T and NK cells with enhanced effector function, leading to durable antitumoral response. These findings suggest SAR'245 potential for the treatment of solid tumors, particularly in combination with inhibitors of PD-1."

IO biomarker • Journal • Oncology • Solid Tumor • CD4 • CD8 • IL2

KEYNOTE-B78: A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203) (clinicaltrials.gov) - P2 | N=138 | Completed | Sponsor: Sanofi | Terminated ➔ Completed

Trial completion • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • MSI

A Study of SAR444245 Combined With Cemiplimab for the Treatment of Participants With Various Advanced Skin Cancers (Pegathor Skin 201) (clinicaltrials.gov) - P1/2 | N=46 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns

Metastases • Trial termination • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

KEYNOTE-B75: A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With HNSCC (Master Protocol) (Pegathor Head and Neck 204) (clinicaltrials.gov) - P2 | N=59 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns.

Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Utilizing pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers to support recommended phase 2 dose (RP2D) selection for phase 1 study of SAR444245 (SAR'245) in patients with advanced solid tumors (SITC 2024) - P1/2 | "The IRB approved the protocol. All participants provided informed consent prior to the initiation of the study."

Biomarker • Clinical • Metastases • P1 data • P2 data • PK/PD data • Oncology • Solid Tumor • CD8 • IL2

KEYNOTE-B71: A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Lung Cancer or Mesothelioma (Pegathor Lung 202) (clinicaltrials.gov) - P2 | N=106 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns.

Trial termination • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

KEYNOTE-C39: A Study of SAR444245 With or Without Other Anticancer Therapies for the Treatment of Adults and Adolescents With Relapsed or Refractory B Cell Lymphoma (Master Protocol) [Pegathor Lymphoma 205] (clinicaltrials.gov) - P2 | N=14 | Terminated | Sponsor: Sanofi | Trial completion date: Jan 2025 ➔ Sep 2024 | Active, not recruiting ➔ Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns.

Trial completion date • Trial termination • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

KEYNOTE-B78: A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203) (clinicaltrials.gov) - P2 | N=138 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns.

Trial termination • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • Squamous Cell Carcinoma • MSI • PD-L1

HAMMER: A Study Evaluating Safety and Therapeutic Activity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors (THOR-707-101) (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Synthorx, Inc, a Sanofi company | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Colon Cancer • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • KRAS

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=258 | Recruiting | Sponsor: Sanofi | N=197 ➔ 258

Combination therapy • Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

A precision engineered interleukin-2 (IL-2) for bolstering CD8+ T- and NK-cell activity without eosinophilia and vascular leak syndrome in non-human primates. (PubMed, Cancer Res Commun) - "We have created a precisely pegylated IL-2 [SAR-444245 (SAR'245) or pegenzileukin, previously THOR- 707] designed for proliferation of target CD8+ T and NK cells for anti-cancer activity, with minimal expansion of anti-target regulatory CD4+ T cells (Tregs) that counter their action, or eosinophils that trigger vascular leak syndrome (VLS)...Ex vivo, SAR'245 enhanced T-cell receptor responses alone and in combination with PD-1 inhibitors without inducing cytokines associated with cytokine release syndrome or VLS. Results support the clinical development of SAR'245 as a drug candidate for the treatment of solid tumors, alone or in combination with PD-1 inhibitory agents."

Journal • Eosinophilia • Oncology • Solid Tumor • CD4 • IL2

KEYNOTE-B75: A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With HNSCC (Master Protocol) (Pegathor Head and Neck 204) (clinicaltrials.gov) - P2 | N=59 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Feb 2025 ➔ Nov 2024

Trial completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=197 | Recruiting | Sponsor: Sanofi | Trial completion date: Dec 2027 ➔ Mar 2028 | Trial primary completion date: Dec 2027 ➔ Jun 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Pegenzileukin, a Selectively Pegylated IL-2 Analog, Enhances Anti-Tumor Function of NK Cells without Activating Regulatory T Cells (ASGCT 2024) - "In vivo administration of pegenzileukin together with K-NK cells improves tumor control and correlates with higher numbers of K-NK cells in peripheral blood. Thus, a combination therapy of adoptive K-NK cells and pegenzileukin has the potential to significantly improve pharmacokinetics of K-NK cells and enhance pharmacodynamics for cancer therapy."

Graft versus Host Disease • Immunology • Oncology • CD8 • IL2

Evaluation of NK cell combination therapies in mouse models of cancer (AACR 2024) - "SAR445419 is a universal off-the-shelf allogeneic human NK cell (hNK) product made using Sanofi's proprietary platform with potential broad application across hematologic and solid tumor indications...We also reported prolonged lifespan of leukemia-bearing animals treated with NK cells and pegenzileukin, a PEGylated non-alpha rhIL‑2 variant engineered to preferentially bind to the IL-2 βγ receptors and promote NK cell function...Obtained results suggest that CD38KO NK cells are resistant to anti-CD38 mAb-mediated fratricide and provide a rationale for the combination of CD38KO NK cells with anti-an CD38 mAb against MM. Overall, these preclinical in vivo studies have a pivotal role in the evaluation of NK cell combination therapies against cancer and reveal their therapeutic potential."

Combination therapy • Preclinical • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • IL2

A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203) (clinicaltrials.gov) - P2 | N=138 | Active, not recruiting | Sponsor: Sanofi | N=280 ➔ 138 | Trial completion date: Mar 2024 ➔ Sep 2024

Enrollment change • Metastases • Trial completion date • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • Squamous Cell Carcinoma • MSI • PD-L1

A Study of SAR444245 With or Without Other Anticancer Therapies for the Treatment of Adults and Adolescents With Relapsed or Refractory B Cell Lymphoma (Master Protocol) [Pegathor Lymphoma 205] (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Sep 2024 ➔ Jan 2025

Trial completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of SAR444245 Combined With Cemiplimab for the Treatment of Participants With Various Advanced Skin Cancers (Pegathor Skin 201) (clinicaltrials.gov) - P1/2 | N=46 | Active, not recruiting | Sponsor: Sanofi | N=80 ➔ 46

Enrollment change • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With HNSCC (Master Protocol) (Pegathor Head and Neck 204) (clinicaltrials.gov) - P2 | N=59 | Active, not recruiting | Sponsor: Sanofi | N=120 ➔ 59 | Trial completion date: Aug 2024 ➔ Feb 2025

Enrollment change • Trial completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Study of SAR444245 With or Without Other Anticancer Therapies for the Treatment of Adults and Adolescents With Relapsed or Refractory B Cell Lymphoma (Master Protocol) [Pegathor Lymphoma 205] (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Sanofi | N=50 ➔ 14

Enrollment change • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Lung Cancer or Mesothelioma (Pegathor Lung 202) (clinicaltrials.gov) - P2 | N=107 | Active, not recruiting | Sponsor: Sanofi | N=160 ➔ 107 | Trial completion date: Feb 2024 ➔ Jan 2025

Enrollment change • Trial completion date • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=197 | Recruiting | Sponsor: Sanofi | N=123 ➔ 197 | Trial completion date: Nov 2028 ➔ Dec 2027 | Trial primary completion date: Nov 2028 ➔ Dec 2027

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203) (clinicaltrials.gov) - P2 | N=280 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Sep 2023 ➔ Mar 2024

Metastases • Trial completion date • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • Squamous Cell Carcinoma • MSI • PD-L1