utomilumab (PF-05082566)

P3, N=61, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=262 --> 61 | Trial completion date: May 2025 --> Sep 2026 | Trial primary completion date: May 2025 --> Sep 2026

P1, N=16, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies.

P3, N=262, Recruiting, Pfizer | Trial completion date: Dec 2025 --> May 2025 | Trial primary completion date: Dec 2025 --> May 2025

P1/2, N=8, Completed, M.D. Anderson Cancer Center | Suspended --> Completed

P2, N=150, Recruiting, Hope Rugo, MD | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1...All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan... This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC.

We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

Moreover, monoclonal antibodies that target-4-1BB, for example, Urelumab and Utomilumab, are widely used in the treatments of B cell non-Hodgkin lymphoma, lung cancer, breast cancer, soft tissue sarcoma, and other solid tumors. As such, a deeper understanding of 4-1BB will contribute to improvements in cancer immunotherapy. This review provides a comprehensive analysis of current 4-1BB studies, with a focus on the use of targeting-4-1BB antibodies and 4-1BB activation domains in CAR-T cells for the treatment of cancer.

Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

P1, N=16, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

P2, N=150, Recruiting, Hope Rugo, MD | Trial completion date: Jul 2023 --> Jun 2024 | Trial primary completion date: Jul 2023 --> Jun 2024

P1/2, N=8, Suspended, M.D. Anderson Cancer Center | Phase classification: P1 --> P1/2 | N=18 --> 8 | Trial completion date: Oct 2022 --> Oct 2023 | Active, not recruiting --> Suspended | Trial primary completion date: Oct 2022 --> Oct 2023

P1b/2, N=405, Terminated, Pfizer | Active, not recruiting --> Terminated; The study was terminated since there was no need for further safety or efficacy data to be collected. The participants having benefit from the Investigational treatments have been moved to a continuation study (NCT05059522)

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.

P2, N=100, Active, not recruiting, Adrienne G. Waks | Recruiting --> Active, not recruiting

P1/2, N=173, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2022 --> Sep 2024

P1, N=42, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

P1/2, N=15, Terminated, Kite, A Gilead Company | Active, not recruiting --> Terminated; Development program terminated

P1/2, N=15, Active, not recruiting, Kite, A Gilead Company | Trial completion date: Sep 2022 --> Dec 2022

Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients.

P1b, N=18, Completed, George W. Sledge Jr. | Active, not recruiting --> Completed | Trial completion date: Oct 2021 --> Feb 2022

P1, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2021 --> Oct 2022 | Trial primary completion date: Oct 2021 --> Oct 2022

This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

Utomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.

P1, N=16, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

P1b/2, N=398, Active, not recruiting, Pfizer | Trial completion date: Apr 2022 --> Feb 2023 | Trial primary completion date: Apr 2022 --> Feb 2023

P2, N=100, Recruiting, Adrienne G. Waks | Trial primary completion date: Jul 2022 --> Jul 2023

P1/2, N=15, Active, not recruiting, Kite, A Gilead Company | Trial completion date: Jun 2022 --> Sep 2022

4-1BB agonizing monoclonal antibodies have thus far failed to progress beyond early clinical development, either due to hepatic toxicities caused by FcγR-crosslinking (urelumab) or due to low clinical activity (utomilumab). When tumor-bearing mice were treated IP with Opal at 1 mg/kg, 7/10 mice exhibited durable cures without significant body weight loss. Taken together, the preclinical data suggests that Opal may exhibit single-agent activity in solid tumors by conditionally activating effector cells in the tumor microenvironment via 4-1BB agonism while concurrently blocking the PD1/PDL1/PDL2 axis.

P2, N=100, Recruiting, Adrienne G. Waks | Trial primary completion date: Jan 2022 --> Jul 2022

P1, N=42, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Patients received a single infusion of 2×10 6 CAR T cells/kg after conditioning chemotherapy with fludarabine and cyclophosphamide. Notably, an apparent association between elevated levels of effector memory T cells and clinical responses was observed. Conclusion Results from ZUMA-11 suggest that 4-1BB agonism with utomilumab affords dose-dependent functional modulation of axi-cel, a tolerable toxicity profile and promising preliminary efficacy.

P1/2, N=173, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Jul 2020 --> Oct 2021 | Trial primary completion date: Jul 2020 --> Oct 2021

P1/2, N=15, Active, not recruiting, Kite, A Gilead Company | Trial completion date: Nov 2021 --> Apr 2022

Early efforts to develop 4-1BB targeted agonists were limited by poor tolerability (Urelumab) or insufficient efficacy (Utomilumab). INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624). Trial Registration INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).

P2, N=100, Recruiting, Ian E. Krop, MD, PhD | Suspended --> Recruiting

P1b/2, N=398, Active, not recruiting, Pfizer | Trial completion date: Feb 2024 --> Apr 2022 | Trial primary completion date: Feb 2024 --> Apr 2022

P2, N=150, Recruiting, Hope Rugo, MD | Trial completion date: Jul 2021 --> Jul 2023 | Trial primary completion date: Jul 2021 --> Jul 2023

P2, N=100, Suspended, Ian E. Krop, MD, PhD | Trial primary completion date: May 2021 --> Jan 2022