feladilimab (GSK3359609)

P3, N=117, Terminated, GlaxoSmithKline | Phase classification: P2/3 --> P3

P3, N=315, Terminated, GlaxoSmithKline | Phase classification: P2/3 --> P3

P1/2, N=464, Recruiting, GlaxoSmithKline | Trial completion date: Feb 2028 --> Feb 2029 | Trial primary completion date: Feb 2025 --> Feb 2026

P2/3, N=118, Terminated, GlaxoSmithKline | Active, not recruiting --> Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

P2/3, N=315, Terminated, GlaxoSmithKline | Active, not recruiting --> Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

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.

P1; Active, not recruiting --> Completed

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 immunomodulation by ICOS and 4-1BB agonists could represent a therapeutic vulnerability for this high-risk subgroup.

A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds.

P2, N=105, Completed, GlaxoSmithKline

P1, N=54, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

P2, N=185, Recruiting, GlaxoSmithKline | N=140 --> 185 | Trial completion date: Jun 2024 --> Jul 2025 | Trial primary completion date: Jun 2024 --> Jul 2025

P2, N=140, Recruiting, GlaxoSmithKline | N=341 --> 140 | Trial completion date: Mar 2025 --> Jun 2024 | Trial primary completion date: Mar 2025 --> Jun 2024

In this substudy, belamaf is combined with feladilimab (GSK3359609), an inducible co-stimulatory T-cell molecule (ICOS, CD278) agonist (aICOS). A total of 23 patients treated with belamaf + aICOS were included in this preliminary analysis. The median (range) of prior lines of therapy was 5 (3–10). The majority of patients (21 [91%]) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 and the remainder (2 [9%]) had an ECOG PS of 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.

P1, N=828, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Jun 2023 | Trial primary completion date: Dec 2024 --> Jun 2023

P2/3, N=314, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P3 --> P2/3 | N=600 --> 314 | Trial completion date: Jul 2023 --> Apr 2023 | Trial primary completion date: Jul 2023 --> Apr 2021

P2/3, N=118, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P3 --> P2/3 | N=640 --> 118 | Trial completion date: Mar 2024 --> May 2023 | Trial primary completion date: Mar 2024 --> Apr 2021

Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC . Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC . Further study is warranted .

To support ongoing and future clinical studies for feladilimab (GSK3359609), a non-depleting IgG4 ICOS agonist antibody currently being evaluated in pivotal clinical trials, we conducted a series of in vivo studies using a rodent surrogate (7E.17G9 mouse [m]IgG1; analogous non-depleting Fc) in ICOS-sensitive (EMT6 breast carcinoma) and ICOS-insensitive (CT26 colon carcinoma) tumor models...Collectively, these data support the combination of ICOS co-stimulation with different checkpoint immunotherapies (doublets and triplets), several of which are currently being evaluated in clinical studies. Moreover, these data demonstrate potential of ICOS co-stimulation with cytotoxic strategies, such as FRT - providing various dosing considerations and a framework future therapeutic intervention strategies.

FE is the first ICOS agonist with reported single-agent activity in ICB exp R/R melanoma, supporting ICOS as a target. FE + PE in combo shows promising clinical activity and manageable safety in R/R melanoma. Continued survival follow-up of ECs is warranted.

Overall, these data support the ongoing pivotal investigation of feladilimab. Moreover, this translational imaging method may be a useful tool to non-invasively monitor CD8+ T cell in response to immunotherapies and understand the temporal relationship between CD8+ T cell flux in tumor and in TDLN.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

No abstract available

No abstract available

P2, N=341, Recruiting, GlaxoSmithKline | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P2, N=341, Recruiting, GlaxoSmithKline | N=105 --> 341

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

P3, N=640, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting

P1, N=54, Active, not recruiting, GlaxoSmithKline | Suspended --> Active, not recruiting | N=162 --> 54

P1, N=162, Suspended, GlaxoSmithKline | Trial primary completion date: Dec 2021 --> Aug 2020

P1; Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

P3, N=640, Not yet recruiting, GlaxoSmithKline

To support the clinical development of GSK3359609 (a hIgG4 ICOS agonist antibody) several in vivo combination studies were conducted using a tool anti-mouse ICOS agonist antibody (clone 7E.17G9). With this in mind, and consistent with ICI, antitumor activity was observed in combination with innate immune modulators (e.g. TLR4 agonist) and chemo/cytotoxic (e.g. carboplatin and paclitaxel) therapies in different syngeneic tumor models. Altogether these data underscore the broad utility of ICOS agonist antibodies as a reliable combination partner for cancer immunotherapy.

Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020...Results - Conclusion - Funding: GlaxoSmithKline (208887). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020...Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Research Funding: GlaxoSmithKline

P2, N=105, Recruiting, GlaxoSmithKline | Active, not recruiting --> Recruiting

P2, N=106, Active, not recruiting, GlaxoSmithKline | Trial completion date: Jan 2022 --> Jun 2024 | Trial primary completion date: Jan 2021 --> Jun 2024

P1, N=162, Suspended, GlaxoSmithKline | Recruiting --> Suspended

P2, N=104, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting

Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Research Funding: GSK

This updated analysis with a more mature dataset shows promising clinical activity that supports further randomized investigation of GSK609 in combination with PE with an OS endpoint in HNSCC. Research Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.