feladilimab (GSK3359609) / GSK - LARVOL DELTA

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=208 | Active, not recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Feb 2029 ➔ Mar 2027 | Trial primary completion date: Feb 2029 ➔ Apr 2025

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

Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Feladilimab (GSK3359609) in Participants With RRMM (clinicaltrials.gov) - P1/2 | N=25 | Active, not recruiting | Sponsor: GlaxoSmithKline

Monotherapy • New P1/2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors. (PubMed, J Immunother Cancer) - "This study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile."

IO biomarker • Journal • P1 data • Fatigue • Hematological Disorders • Oncology • Solid Tumor • CD4 • CD8 • ICOS

CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting. (PubMed, Bioorg Med Chem Lett) - "Key therapeutic approaches include CTLA-4-Ig fusion proteins (abatacept, belatacept) for autoimmune diseases, ICOS agonists (feladilimab, vopratelimab) to enhance anti-tumor immunity, and bispecific CD28-engaging antibodies (CD28xCD3, CD28xPSMA) for cancer immunotherapy. By integrating structural insights with translational drug development, this review provides a framework for optimizing CD28- and ICOS-targeted therapies. Further advancements in biologics, peptide-based inhibitors, and immune checkpoint modulation will enhance the precision and efficacy of immunotherapeutic strategies."

Journal • Review • Immunology • Oncology • CTLA4 • ICOS

Platform Trial of Novel Regimens Versus Standard of Care (SoC) in Participants With Non-small Cell Lung Cancer (NSCLC) - Sub-study 2 (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: GlaxoSmithKline | Initiation date: Jan 2019 ➔ Mar 2021

Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Platform Trial of Novel Regimens Versus Standard of Care (SoC) in Participants With Non-small Cell Lung Cancer (NSCLC) - Sub-study 2 (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: GlaxoSmithKline

New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=209 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | Phase classification: P1/2 ➔ P2 | N=464 ➔ 209 | Trial primary completion date: Feb 2026 ➔ Feb 2029

Enrollment change • Enrollment closed • Monotherapy • Phase classification • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Platform Trial of Novel Regimens Versus Standard of Care (SoC) in Participants With Non-small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P2 | N=176 | Completed | Sponsor: GlaxoSmithKline | Recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ May 2024 | Trial primary completion date: Jul 2025 ➔ May 2024

Trial completion • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

INDUCE-4: Study of GSK3359609 With Pembrolizumab and 5-fluorouracil (5-FU)-Platinum Chemotherapy in Participants With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P3 | N=117 | Terminated | Sponsor: GlaxoSmithKline | Phase classification: P2/3 ➔ P3

Phase classification • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

INDUCE-3: Study of GSK3359609 and Pembrolizumab in Programmed Death Receptor 1-ligand 1 (PD-L1) Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P3 | N=315 | Terminated | Sponsor: GlaxoSmithKline | Phase classification: P2/3 ➔ P3

Combination therapy • IO biomarker • Metastases • Phase classification • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors. (PubMed, Cancer Immunol Immunother) - P1/2 | "Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2."

Combination therapy • IO biomarker • Journal • Metastases • P1/2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P1/2 | N=464 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Feb 2028 ➔ Feb 2029 | Trial primary completion date: Feb 2025 ➔ Feb 2026

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

INDUCE-4: Study of GSK3359609 With Pembrolizumab and 5-fluorouracil (5-FU)-Platinum Chemotherapy in Participants With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2/3 | N=118 | Terminated | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

Combination therapy • Metastases • Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

INDUCE-3: Study of GSK3359609 and Pembrolizumab in Programmed Death Receptor 1-ligand 1 (PD-L1) Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2/3 | N=315 | Terminated | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

Combination therapy • IO biomarker • Metastases • Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade. (PubMed, Cancer Res Commun) - P1 | "In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors."

Checkpoint block • Checkpoint inhibition • Combination therapy • IO biomarker • Journal • P1 data • Oncology • Solid Tumor • CTLA4 • ICOS

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1 | N=829 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI

A sub-population of cells expressing MYC and BCL2 without BCL6 refines the definition of double expressor lymphoma (DEL) (ICML 2023) - "However, with larger numbers of DEL cases available in mRNA-based measurement cohorts, there was a statistically significant stratification for PFS (GSE117556: OS, p = 0.084, PFS, p = 0.031; GOYA: OS, p = 0.065, PFS, p = 0.047), suggesting that the following formula refines the current DEL definition and improves its prognostic value: Using a pan-immune protein-marker DSP panel, we identified that the T-cell immune regulators ICOS and 4-1BB were negatively correlated with M+2+6- percentage extent (r = −0.27, p = 0.0046; r = −0.22, p = 0.019, respectively), suggesting a potential role for ICOS or 4-1BB stimulatory therapeutics (e.g. feladilimab, utomilumab) in combination with chemotherapy for high M+2+6- cases. A simple mathematical formula for estimation of MYC+BCL2+BCL6- cells in DLBCL refines the DEL diagnosis, and could be of value in selecting high risk DLBCL for trials of novel agents. High M+2+6- DLBCL display unique T-cell infiltrates, and..."

Clinical • IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CD4 • CD8 • ICOS • MYC

[VIRTUAL] MODULE 3: New Directions in the Management of UBC (ASCO 2021) - "Available data from the Phase I/II CheckMate 032 trial of nivolumab alone or in combination with ipilimumab in the cohort of patients with advanced UBC Ongoing Phase III trials (eg, CheckMate 901, NILE) evaluating anti-PD-1/PD-L1 antibodies in combination with other systemic therapies as first-line therapy for patients with unresectable locally advanced or metastatic UBC Design, eligibility criteria and key endpoints of the ongoing Phase III PROOF 302 trial of the oral FGFR inhibitor infigratinib as adjuvant therapy for patients with MIBC harboring susceptible FGFR3 alterations Published research findings and ongoing evaluations of other FGFR-targeted agents (eg, pemigatinib, rogaratinib, vofatamab, LY3076226, futibatinib) in UBC Clinical rationale for the ongoing evaluation of enfortumab vedotin in combination with an immune checkpoint inhibitor as neoadjuvant therapy for cisplatin-eligible patients with MIBC (KEYNOTE-B15/EV-304) Potential role of the antibody-drug..."

Immune Modulation • Inflammation • Oncology • FGFR3 • ICOS

A phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumours (NCT03447314) (ESMO 2019) - P1; "The current study will evaluate GSK1795091 with immunotherapies that have highly complementary mechanisms of action and supporting preclinical data (e.g. GSK3174998 [an OX40 agonist], GSK3359609 [an ICOS agonist], or pembrolizumab [a PD-1 inhibitor]) with the aim of generating greater antitumor activity than with monotherapy. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline."

Clinical • Combination therapy • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Preclinical evaluation of a non-depleting, first-in-class humanized IgG4 agonist anti-ICOS antibody (ESMO 2018) - "IgG4PE provides the optimal isotype for delivering ICOS agonism whilst reducing the risk of depletion of ICOS positive effector TC. The comprehensive preclinical data package generated, supports clinical testing of the H2L5 IgG4PE ICOS agonist antibody (GSK3359609), currently being investigated alone and in combination with pembrolizumab, in a first in human clinical study (INDUCE-1)."

IO biomarker • PD(L)-1 Biomarker • Preclinical • Solid Tumor

First in Human Study with GSK3359609 [GSK609], Inducible T cell Co-stimulator (ICOS) Receptor Agonist in Patients [Pts] with Advanced, Solid Tumors: Preliminary Results from INDUCE-1 (ESMO 2018) - P1; " INDUCE-1 evaluates safety, PK, PD, and antitumor activity of GSK609 given as an intravenous (IV) infusion every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab [P] Q3W (Part 2). GSK609 +/- P was well tolerated; MTD was not reached. AEs were manageable and most were unrelated to study treatment. Complete safety, PD and clinical activity data from DE and PK/PD will be presented."

Clinical • P1 data • Solid Tumor

DREAMM-5 platform trial: Belantamab Mafodotin (GSK2857916; belamaf; BLENREP) in combination with five different novel agents in patients (Pts) with Relapsed/ Refractory Multiple Myeloma (RRMM) (DGHO 2021) - P1/2 | "Sub-study 1 (combination with GSK3174998, OX40 agonist Ab) is closed to enrolment. Sub-studies 2 (combination with GSK3359609, feladilimab, ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist) are open to enrolment...Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively. Encore Statement: Presented at 26th Congress of the European Hematology Association (Richardson et al, 2021); submitted with permission of original authors."

Clinical • Combination therapy • IO biomarker • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • ICOS • PD-1

[VIRTUAL] Dreamm-5 Platform Trial: Belantamab Mafodotin (Belamaf) in Combination with Four Different Novel Agents in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2020) - P2 | "Substudies 1 (combination with GSK3174998, OX40 agonist antibody), 2 (combination with GSK3359609, ICOS agonist antibody), and 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor) are currently open to enrollment. Substudy 4 (combination with dostarlimab; PD-1 antagonist antibody) is under review...Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seattle Genetics; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics. Figure: DREAMM-5 study design"

Clinical • Combination therapy • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD38 • ICOS

INDUCE-1: Cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (Oncology Tube) - "Erminia Massarelli, MD...discusses INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors."

Video

[VIRTUAL] INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. (ASCO 2020) - P1 | "The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted."

Clinical • Acute Kidney Injury • Head and Neck Cancer • Hematological Disorders • Immunology • Mucositis • Nephrology • Neutropenia • Oncology • Pain • Renal Disease • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Stomatitis