Clinical Activity and Durable Responses Observed With MEDI-570 in R/R T-cell Lymphomas

Julio Chavez, MD, MS

In a phase 1 study (NCT02520791) of patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma (PTCL), the anti-inducible T-cell co-stimulator (ICOS) monoclonal antibody MEDI-570 demonstrated activity, durable responses, safety, and tolerability, according to a presentation at the 2020 American Society of Hematology Annual Meeting.

Clinical activity was seen at all dose levels and mainly in those with AITL histology; 4 out of 12 patients with AITL achieved at least a partial response. Durable response were observed regardless of the dose level received. The investigators determined that the recommended phase 2 dose of MEDI-570 was 3 mg/kg administered intravenously every 3 weeks.

Evaluation of the treatment-emergent adverse events (AEs) showed that MEDI-570 was well tolerated. There were no dose-limiting toxicities, such as cryptococcosis or disseminated thrombocytopenia, or grade 3 infections, and the maximum tolerated dose was not reached. The most common grade 1/2 AEs were infusion related reactions in 8 patients (47%) and fatigue, constipation, and nausea all in 5 patients (30%) each. The most common grade 3/4 treatment-emergent AEs were lymphopenia in 11 patients (65%) and decreased CD4 positivity in 5 patients (30%).

For this first-in-human trial, 17 patients received MEDI-570 after at least 1 line of prior therapy as of the data cutoff. The trial’s escalation and expansion phases included 6 dose levels (DLs) given every 3 weeks. DL-1 was 0.005 mg/kg of MEDI-570, DL1 was 0.01 mg/kg, DL2 was 0.1 mg/kg, DL3 was 0.3 mg/kg, DL4 was 1 mg/kg, and DL5 was 3 mg/kg. Treatment was continued for 12 cycles, until disease progression, or until toxicity.

MEDI-570, an afucosylated fully human IgG kappa monoclonal antibody against the ICOS ligand, eliminates ICOS expressing T cells, such as T follicular helper cells. ICOS, which is a T-cell enhancer, is upregulated in activated T cells such as effector T cells, Tfh cells, and regulatory T cells. At the beginning of the study, investigators hypothesized that this treatment could effectively treat tumors with increased Tfh cells including AITL, follicular type PTCL, and other T-cell lymphoma subtypes by targeting ICOS.

“MEDI-570 exposure resulted in reduction of CD4-positive, ICOS-positive T-cells, reflecting its effects on memory T cells and T follicular helper [Tfh] cells,” Julio C. Chavez, MD, MS, from the University of South Florida H. Lee Moffitt Cancer Center and Research Institute, said in his poster presentation.

In T cell subpopulations analyses, MEDI-570 caused reductions of CD4-positive T cells on days 7 through 21 post infusion. B cells and natural killer cells were not affected by this treatment.

Pharmacokinetic studies showed that exposure of MEDI-570 increased in a dose-dependent fashion and a longer half-life was reported at higher dose levels, although further pharmacokinetic analyses of DL4 and DL5 are still pending.

Primary end points were safety and tolerability, maximum tolerated dose, and the recommended phase 2 dose. Secondary end points included pharmacokinetic immunogenicity of the study drug, overall response rate, and progression-free survival. Patients had to have AITL or follicular type PTCL a performance status of 0 or 1 and CD4 T-cell count of at least 100.

The median age of the patients was 63 (range, 29-80) and the participants included 5 women and 13 men. These heavily pretreated patients had a median of 7 prior therapies (range, 1-16). Three patients (18%) had prior autologous hematopoietic cell transplantation. The majority of patients (n = 12) had AITL.

The dose-expansion phase of the study is continuing and a new treatment arm has been added for patients with newly diagnosed AITL who are not candidates for chemotherapy.

_Reference:

_{Chavez JC, Foss FM, William BM, et al. A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930). Poster presented at: 62nd American Society of Hematology Annual Meeting and Exhibition; December 5-8, 2020; Virtual. Abstract 1151. https://bit.ly/36L5BE7}