INCAGN1949 / Agenus, Incyte - LARVOL DELTA

Addition of GITR Agonist to a Dark Matter Cancer Vaccine and anti-PD-1 Increases Regulatory T cell Numbers Without Appearing to Impact Therapeutic Efficacy (SITC 2025) - "Here we combined treatment groups for analysis of response to treatment and evaluated changes in PBMC.Methods Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) were randomized to receive a heterologous prime-boost regimen of DPV-001 with sequenced d.PD-1 (retifanlimab every 4 weeks), with or without a GITR agonist (INCAGN-1949 every 2 weeks). This occurred in the absence of a significant increase in the absolute numbers of CD3, CD4, or CD8 T cells.Conclusions DPV-001 in combination with delayed PD-1 blockade ± GITR agonist demonstrated promising clinical activity in HNSCC, with response rates of 56% in PD-1 naïve and 33% in PD-1 refractory patients. While not appearing to impact clinical efficacy of the treatment, the significant increase in peripheral blood Treg numbers in patients receiving GITR agonist underscores the complexities that need to be appreciated when developing combination immunotherapies."

Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8

Off-the-shelf dark matter immunotherapy in head & neck cancer: mechanistic insights and clinical efficacy (SITC 2024) - P1 | "Methods Patients were randomized to receive heterologous prime-boost DPV-001 + sequenced d.PD-1 (retifanlimab Q4W) +/- GITR agonist (INCAGN-1949 Q2W). Ongoing studies are directed at unraveling the nature of the antigens recognized (canonical or dark matter), and whether they persist. Ethics Approval This study was approved by Providence Health System's Ethics Board; approval number 2020000480."

Clinical • Late-breaking abstract • Head and Neck Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

An off-the-shelf multivalent vaccine containing cancer's dark matter, DPV-001, combined with PD-1 +/- GITR in head & neck cancer: safety, efficacy, and immunodynamics from the phase 1 GITRVax trial (AACR 2024) - "Preclinical studies identified increased therapeutic efficacy when this vaccine strategy was combined with anti-PD-1 and anti-GITR, leading to this clinical trial for patients with advanced or metastatic HNSCC. Following safety run-in, eligible pts were randomly assigned 1:1 to receive DPV-001 +/- GITR agonist mAb (INCAGN-1949; q2wks). All received sequenced PD-1 mAb (retifanlimab; q4wks) starting D15... This 18 pt trial of DPV-001 and sequenced PD-1 +/- GITR shows a promising RR and evidence of increased activation and expansion of effector T cells in PBL and tumor. Upregulation of LAG-3 and TIM3 by T cells that infiltrate the tumor and have increased in number, provide a rationale for including inhibitors for both in this treatment strategy. Current efforts include evaluating whether immune responses target shared non-canonical alternative neoantigens, or Dark Matter, contained in DPV-001, and whether synchronized antibody and cellular response is evidenced."

Clinical • IO biomarker • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • GZMB • HAVCR2 • IFNG • LAG3 • PD-1

Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma (AACR 2022) - P1 | "Here we report preliminary immunological analyses of patients enrolled in a first-in-human immunotherapy-trio study of multivalent autophagosome vaccine (DPV-001), with sequenced checkpoint inhibition (anti-PD-1; retifanlimab), with/without anti-GITR agonist (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024). Peripheral blood (PB) and sera are collected regularly and PB are evaluated by flow cytometry. We previously reported immunological monitoring of a phase I/II trial of an autophagosome cancer vaccine (DPV-001) containing more than 300 shared cancer antigens, as adjuvant therapy for NSCLC. Vaccination induced or augmented immune responses to more than 50 cancer antigens shared with head and neck squamous cell carcinoma (HNSCC). Preclinical studies combining this cancer vaccine with αGITR agonist and αPD-1 augmented therapeutic efficacy [PMID: 31747946], and provided the rationale for the current study."

P1 data • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8

Trial in progress: First-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma (AACR 2023) - P1 | "We hypothesize that addition of aGITR to DPV-001 vaccine will augment expansion of reactive CD4 and CD8 T cells, attenuate contraction of this response, and improve the therapeutic effect of treatment, and will result in the development of a coordinated T and B cell response to some of the same proteins, detectable using a cutting-edge seromics approach, as a window to TCR target identification for immunodynamic tracking of induced anti-cancer responses at an advanced level. Patient recruitment began in August 2022, for this first-in-human immunotherapy-trio study of DPV-001, with sequenced checkpoint inhibition (aPD-1 mAb; retifanlimab), with or without aGITR agonist mAb (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024)...Initial safety lead-in (n = 3+3 per arm), will be followed by phase Ib expansion of one/both arms if immunologically promising, 28 patients per arm, futility if <4/15 responses.Study DrugsCyclophosphamide 300mg/m2 IV, priming Day..."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • TNFA

CMP-001 and INCAGN01949 for Patients With Stage IV Pancreatic Cancer and Other Cancers Except Melanoma (clinicaltrials.gov) - P1/2 | N=2 | Terminated | Sponsor: University of Southern California | N=42 ➔ 2 | Trial completion date: Apr 2024 ➔ Dec 2022 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2023 ➔ Dec 2022; Study drug no longer available

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatology • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BRCA

INCAGN1949, an anti-OX40 antibody with an optimal agonistic profile and the ability to selectively deplete intratumoral regulatory T cells (AACR 2017) - P1/2; "The functional in vitro and in vivo attributes of INCAGN1949 make it suitable for clinical development. It is currently under evaluation in a Phase 1/2 study in subjects with advanced or metastatic tumors (NCT02923349)."

Biosimilar • Inflammation • Oncology

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1/2 | "No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors."

Journal • P1/2 data • Fatigue • Gallbladder Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immune Modulation • Immunology • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors (J Immunother Cancer) - P1/2 | N=87 | NCT02923349 | Sponsor: Incyte Biosciences International Sàrl | "Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers....One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels."

P1/2 data • Biliary Cancer • Biliary Tract Cancer • Cervical Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer

CMP-001 and INCAGN01949 for Patients With Stage IV Pancreatic Cancer and Other Cancers Except Melanoma (clinicaltrials.gov) - P1/2; N=42; Recruiting; Sponsor: University of Southern California; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Gastrointestinal Cancer • Hepatology • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BRCA

CMP-001 and INCAGN01949 for Patients With Stage IV Pancreatic Cancer and Other Cancers Except Melanoma (clinicaltrials.gov) - P1/2; N=42; Not yet recruiting; Sponsor: University of Southern California; Trial completion date: Jul 2023 ➔ Jul 2024; Initiation date: Jul 2020 ➔ Jul 2021; Trial primary completion date: Jul 2022 ➔ Jul 2023

Clinical • Combination therapy • Trial completion date • Trial initiation date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BRCA

CMP-001 and INCAGN01949 for Patients With Stage IV Pancreatic Cancer and Other Cancers Except Melanoma (clinicaltrials.gov) - P1/2; N=42; Not yet recruiting; Sponsor: University of Southern California; Trial completion date: Dec 2022 ➔ Jul 2023

Clinical • Combination therapy • Trial completion date • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BRCA

CMP-001 and INCAGN01949 for Patients With Stage IV Pancreatic Cancer and Other Cancers Except Melanoma (clinicaltrials.gov) - P1/2; N=42; Not yet recruiting; Sponsor: University of Southern California

Clinical • Combination therapy • New P1/2 trial • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BRCA

Incyte’s targeted therapy and immuno-oncology portfolio to be featured in 20 Abstracts at the AACR Annual Meeting 2017 (Incyte Press Release) - "Incyte...announces that 20 abstracts from its research and development portfolio will be presented at the upcoming 2017 [AACR Annual Meeting]...These abstracts include a clinical data presentation from the dose-escalation phase of the Company’s ongoing trial of its selective FGFR 1/2/3 inhibitor (INCB54828), and well as preclinical data from its small molecule inhibitor programs targeting PI3Kδ (INCB50465), LSD1 (INCB59872), JAK1 (INCB52793), BRD/BET (INCB54329 and INCB57643) and FGFR4 (INCB62079) and from its epacadostat, OX40 (INCAGN1949) and GITR (INCAGN1876) immuno-oncology programs."

Anticipated clinical data • Anticipated conference • Anticipated preclinical • Oncology

Incyte reports 2018 first-quarter financial results and updates on key clinical programs (Incyte Press Release) - "Status update: [1] INCAGN1876 (GITR): Dose escalation completed; [2] INCAGN1949 (OX40):  Dose escalation completed; [3] INCAGN2390 (TIM-3): Expected to enter clinical trials in 2018; [4] INCAGN2385 (LAG-3): Expected to enter clinical trials in 2018."

New trial • Trial status • Oncology

A Phase 1/2, Open-Label, Dose-Escalation, Safety Study of INCAGN01949 in Subjects With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2; N=157; Recruiting; Sponsor: Incyte Europe Sàrl; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Endometrial Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma

Incyte: Q2 FY 2016 Results (Incyte) - Anticipated initiation of P1/2 trial in solid tumors in H2 2016 

Anticipated new trial • Oncology

INCAGN1949: Patent expiry in US in 2037 and EU in 2036 (Agenus Inc.) - Annual Report 2019

Patent

A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies (clinicaltrials.gov) - P1/2; N=52; Completed; Sponsor: Incyte Biosciences International Sàrl; Active, not recruiting ➔ Completed; Trial completion date: Jul 2020 ➔ Nov 2019

Clinical • Combination therapy • Trial completion • Trial completion date • PD-1

A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies (clinicaltrials.gov) - P1/2; N=52; Active, not recruiting; Sponsor: Incyte Biosciences International Sàrl; Trial completion date: Aug 2019 ➔ Jul 2020; Trial primary completion date: Aug 2019 ➔ Nov 2019

Clinical • Combination therapy • Trial completion date • Trial primary completion date

A Phase 1/2, Open-Label, Dose-Escalation, Safety Study of INCAGN01949 in Subjects With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2; N=87; Completed; Sponsor: Incyte Biosciences International Sàrl; Active, not recruiting ➔ Completed

Trial completion

A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies (clinicaltrials.gov) - P1/2; N=52; Active, not recruiting; Sponsor: Incyte Biosciences International Sàrl; Trial completion date: Mar 2019 ➔ Jun 2019; Trial primary completion date: Mar 2019 ➔ Jun 2019

Clinical • Combination therapy • Trial completion date • Trial primary completion date

Incyte reports 2018 second quarter financial results and updates on key clinical programs (Businesswire) - "Status updates: [1] INCMGA0012: Phase 2 trials (MSI-high endometrial cancer, merkel cell carcinoma, anal cancer) expected to begin in 2018; [2] INCB57643 (BRD): Development discontinued after preclinical safety finding; [3] INCAGN1876 (GITR) & INCAGN1949 (OX40): Dose escalation completed; development expected to focus on combination therapy; [4] INCAGN2390 (TIM-3): Expected to enter clinical trials in 2018.INCAGN2385 (LAG-3)2Phase 1/2 dose-escalation."

Discontinuation • New P2 trial • New trial • Trial status

A Phase 1/2, Open-Label, Dose-Escalation, Safety Study of INCAGN01949 in Subjects With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2; N=87; Active, not recruiting; Sponsor: Incyte Biosciences International Sàrl; Trial primary completion date: Dec 2018 ➔ Mar 2019

Clinical • Trial primary completion date