tuparstobart (INCAGN2385) / Incyte, Agenus, Xoma - LARVOL DELTA

Retifanlimab (Anti–PD-1 mAb) alone or in combination with Anti-LAG3 ± Anti-TIM3 mAbs In previously untreated, recurrent and/or metastatic (R/M) PD-L1+ HNSCC: A double-blind randomised controlled phase II trial (ESMO 2025) - P2 | "Methods Pts were randomised (1:1:1) to retifanlimab (RETI) alone, or RETI with tuparstobart (anti-LAG3 mAb; doublet tx) or RETI + tuparstobart and verzistobart (anti-TIM3 mAb; triplet tx). Conclusions This randomised phase 2 trial showed that adding anti-LAG3 ± anti-TIM3 did not significantly improve PFS vs RETI alone in pts with previously untreated R/M PD-L1+ HNSCC. Median PFS with RETI alone exceeded historical data from studies of other anti–PD-1 tx in R/M HNSCC."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • PD-L1

Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=61 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Trial completion • Melanoma • Oncology • Solid Tumor • BRAF

Study of Retinfanlimab in Combination With INCAGN02385 and INCAGN02390 as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P2 | N=176 | Active, not recruiting | Sponsor: Incyte Biosciences International Sàrl | Trial completion date: Jun 2025 ➔ Jul 2026

Trial completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Incyte To Present Initial Data for its TGFβR2×PD-1-directed Bispecific Antibody (INCA33890) and its Selective Inhibitor of G12D-mutated KRAS (INCB161734) at the European Society of Medical Oncology (ESMO) Congress 2025 (Incyte Press Release) - "Details on the abstracts accepted for oral presentation at ESMO include: (i) INCB161734 (KRAS G12D)​: Preliminary Phase 1 Results Of INCB161734, A Novel Oral KRAS G12D Inhibitor, In Patients With Advanced Or Metastatic Solid Tumors​ (...Abstract #916O); (ii) INCA33890 (PD-1/TGFβR2): A Phase 1 Study Of INCA33890, A PD-1/Tgfβr2 Bispecific Antibody, For Advanced Solid Tumours​ (...Abstract #1522); (iii) INCAGN2385 (LAG-3)​: Retifanlimab (Anti–PD-1 Mab) Alone Or In Combination With Anti-LAG3 ± Anti-TIM3 Mabs In Previously Untreated, Recurrent And/Or Metastatic (R/M) PD-L1+ HNSCC: A Double-Blind Randomised Controlled Phase 2 Trial (...Abstract #1325)."

Clinical data • Squamous Cell Carcinoma of Head and Neck

First-in-human phase I open-label study of the LAG-3 antagonist antibody INCAGN02385 in patients with select advanced or metastatic solid tumors. (PubMed, Oncologist) - "INCAGN02385 exhibited linear PK and preliminary evidence of disease control in this heavily pretreated population, consistent with other LAG-3-targeting monotherapies. A 350-mg Q2W dose was selected for phase II studies that will focus on combinations of INCAGN02385 with other ICIs."

IO biomarker • Journal • P1 data • Fatigue • Oncology • Pain • Pneumonia • Solid Tumor • CD4 • CD8 • CTLA4 • LAG3

POD1UM-204: Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (clinicaltrials.gov) - P2 | N=206 | Active, not recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Apr 2025 ➔ Apr 2026

dMMR • MSI-H • Trial primary completion date • Endometrial Cancer • Oncology • Solid Tumor • MSI • PD-L1 • POLE

Trick-MCC: Final results from the proof-of-concept investigator-initiated study of combination therapy with anti–PD-1, anti–LAG-3, and anti–TIM-3 in participants with advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma (NCT06056895). (ASCO 2025) - P2 | " TRICK-MCC (Triple Immune Checkpoint Inhibition in MCC) is an investigator initiated, single center, proof-of-concept clinical trial studying concurrent treatment with anti-PD-1 (retifanlimab, q4w), anti-LAG3 (tuparstobart, q2w) and anti-TIM-3 (verzistobart, q2w) in patients with advanced/metastatic MCC that progressed after PD-(L)1 therapy. Concurrent triple immune checkpoint blockade of PD-1, LAG-3 and TIM-3 appears to be generally well tolerated and associated with clinical activity in our cohort of patients with PD-(L)1 refractory MCC. Our data suggests TIM-3 and LAG-3 are contributing to immune evasion in a subset of patients with PD-(L)1 resistant MCC, providing support for further investigation of these pathways in larger trials."

Clinical • Combination therapy • IO biomarker • Metastases • CNS Disorders • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • CD8

TRICK-MCC: Triple Immune Checkpoint Inhibition for Advanced or Metastatic PD-(L)1 Refractory Merkel Cell Carcinoma (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: University of Washington | N=20 ➔ 12 | Trial completion date: Dec 2029 ➔ Apr 2027 | Trial primary completion date: Dec 2029 ➔ Jan 2027 | Recruiting ➔ Active, not recruiting

Checkpoint inhibition • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

POD1UM-204: Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (clinicaltrials.gov) - P2 | N=206 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=300 ➔ 206

Combination therapy • Enrollment change • Enrollment closed • Metastases • Endometrial Cancer • Oncology • Solid Tumor • MSI • PD-L1 • POLE

PD-1, LAG-3 and TIM-3 Checkpoint Blockade in DLBCL (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: University of Alabama at Birmingham | N=18 ➔ 0 | Not yet recruiting ➔ Withdrawn

CAR T-Cell Therapy • Checkpoint block • Checkpoint inhibition • Enrollment change • Trial withdrawal • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Incyte drops pair of PD-L1 drugs as part of 2nd pipeline clear-out this year (FierceBiotech) - "The latest list of discontinued assets includes both of Incyte’s oral, small-molecule PD-L1 inhibitors that were being assessed in phase 1 trials. One of these, INCB99280, was being evaluated in an early-stage solid tumor trial, and the biotech had already set out plans for a phase 1/1b trial in KRASG12C-mutated solid tumors in combination with Bristol Myers Squibb’s Krazati. The other scrapped PD-L1 inhibitor, dubbed INCB99318, was also in a phase 1 solid tumor trial. Also on the chopping block are a couple of LAG3 drug candidates. One of these is a LAG-3 monoclonal antibody dubbed INCAGN2385 that was being developed with Agenus. The other was a bispecific anti–PD1 and anti–LAG-3 antibody dubbed INCA32459 that was being developed with Merus and had undergone a phase 1 study in select advanced malignancies....Finally, Incyte has removed a TIM-3 monoclonal antibody dubbed INCAGN2390, which was another product of the Merus collaboration."

Discontinued • Oncology • Solid Tumor

Study of Retinfanlimab in Combination With INCAGN02385 and INCAGN02390 as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P2 | N=176 | Active, not recruiting | Sponsor: Incyte Biosciences International Sàrl | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2024 ➔ Jun 2025 | Trial primary completion date: May 2024 ➔ Feb 2025

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Ligand Reports First Quarter 2024 Financial Results (Businesswire) - "On May 7, Ligand announced a $100 million royalty financing agreement with Agenus, Inc. Under the terms of the agreement, in exchange for an initial $75 million payment, Ligand will receive 18.75% of the royalties and 31.875% of the future milestones on six Agenus-partnered oncology programs including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma)."

Financing • Licensing / partnership • Oncology

TRICK-MCC: A proof-of-concept, investigator-initiated study of combination therapy with anti–PD-1, anti–LAG-3, and anti–TIM-3 in participants with advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma. (ASCO 2024) - P2 | " TRICK-MCC (Triple Immune Checkpoint Inhibition in MCC) is an investigator initiated, Phase 2 clinical trial investigating concurrent treatment with anti-PD-1 (retifanlimab), anti-LAG3 (INCAGN02385) and anti-TIM-3 (INCAGN02390) in patients with advanced/metastatic MCC that has progressed after treatment with anti-PD-(L)1. Planned correlative studies aim to better characterize the prevalence and significance of cancer-specific T cell exhaustion (through rigorous study of MCPyV-specific T cells), the immunologic effects of triple ICI, and alternative mechanisms of PD-(L)1 resistance beyond T cell exhaustion in PD-(L)1 resistant tumors. We hope to gain insights that are broadly applicable to solid tumor immunotherapy."

Combination therapy • IO biomarker • Metastases • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • CD8

PD-1, LAG-3 and TIM-3 Checkpoint Blockade in DLBCL (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: University of Alabama at Birmingham

CAR T-Cell Therapy • Checkpoint block • Checkpoint inhibition • New P1 trial • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Optimus: An Umbrella Study to Determine the Safety and Efficacy of Various Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma (clinicaltrials.gov) - P2 | N=30 | Terminated | Sponsor: Incyte Corporation | Trial completion date: Jun 2024 ➔ Jan 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2024 ➔ Jan 2024; Business Decision. No safety concerns contributed to this decision.

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=61 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=146 ➔ 61

Enrollment change • Enrollment closed • Melanoma • Oncology • Solid Tumor • BRAF

Optimus: An Umbrella Study to Determine the Safety and Efficacy of Various Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=45 ➔ 30

Combination therapy • Enrollment change • Enrollment closed • Monotherapy • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

POD1UM-204: Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Aug 2023 ➔ Apr 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Solid Tumor • MSI • PD-L1 • POLE

Triple Immune Checkpoint Inhibition for Advanced or Metastatic PD-(L)1 Refractory Merkel Cell Carcinoma (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: University of Washington | Not yet recruiting ➔ Recruiting

Checkpoint inhibition • Combination therapy • Enrollment open • Metastases • Gastrointestinal Cancer • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Triple Immune Checkpoint Inhibition for Advanced or Metastatic PD-(L)1 Refractory Merkel Cell Carcinoma (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: University of Washington

Checkpoint inhibition • Combination therapy • Metastases • New P2 trial • Gastrointestinal Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=146 | Recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Jul 2023 ➔ Aug 2025

Combination therapy • Metastases • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF

Triple PD-1, LAG-3 and TIM-3 inhibition in solid tumors (YouTube) - "Omid Hamid, MD...comments on results from a Phase I/II trial (NCT04370704) of retifanlimab, INCAGN02385, and INCAGN02390 in patients with advanced solid tumors...Further research will assess this combination in the first-line setting in patients with treatment-naive melanoma. This interview took place at the American Society of Clinical Oncology (ASCO) 2023 Annual Congress in Chicago, IL."

Interview • Video

Phase 2 trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) as first-line treatment in patients with PD-L1–positive recurrent/metastatic squamous cell carcinoma of the head and neck. (ASCO 2023) - P2 | "Patient enrollment is ongoing. Clinical trial information: NCT05287113."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Head and Neck Cancer • Immune Modulation • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors. (ASCO 2023) - P1/2 | "Doublet anti–LAG-3 + anti–TIM-3 and triplet anti–LAG-3 + anti–TIM-3 + retifanlimab regimens in the study were generally well tolerated in heavily pretreated pts, with a safety profile consistent with that of CP monotherapy and no novel toxicities. Optimal doses of both combinations are to be further evaluated in the ongoing study in first-line tx of melanoma. Clinical trial information: NCT04370704."

Clinical • Combination therapy • IO biomarker • Metastases • P1/2 data • Anemia • Cardiovascular • Hematological Disorders • Infectious Disease • Melanoma • Novel Coronavirus Disease • Oncology • Septic Shock • Solid Tumor • Vasculitis