1549TiP DeLLphi-303: Phase Ib first-line combination study of tarlatamab, a DLL3-targeting half-life extended bispecific T-cell engager (HLE BiTE®), with carboplatin, etoposide, and PD-L1 inhibition in extensive stage small cell lung cancer (ES-SCLC)

Background: The inhibitory Notch ligand, delta-like ligand 3 (DLL3), is a compelling therapeutic target due to its aberrant expression on the cell surface in most small cell lung cancer (SCLC). Tarlatamab (AMG 757) is a half-life extended bispecific T-cell engager (HLE BiTE®) molecule designed to specifically bind DLL3 on target cancer cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. Data from an ongoing first-in-human monotherapy study show acceptable safety with evidence of tarlatamab efficacy in patients with relapsed/refractory SCLC (NCT03319940). Adding programmed death ligand 1 (PD-L1) inhibitors to first-line platinum chemotherapy is the emerging standard-of-care (SOC) in ES-SCLC and preclinical data suggests increased antitumor activity of BiTE molecules when combined with PD-1/PD-L1 inhibition or chemotherapy.1 These data support a clinical trial of tarlatamab combined with frontline carboplatin, etoposide, and PD-L1 inhibition in ES-SCLC. Trial design: This is a phase 1b, multicenter, open-label study evaluating tarlatamab in combination with first-line SOC chemo-immunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in two separate settings: A) In combination with carboplatin, etoposide, and a PD-L1 inhibitor followed by maintenance cycles of tarlatamab plus PD-L1 inhibitor, and B) In combination with PD-L1 inhibitor following SOC chemo-immunotherapy as a maintenance only approach. Key eligibility criteria include patients with histologically or cytologically confirmed ES-SCLC with no prior systemic treatment (except as specified in protocol) and ECOG performance status ≤1. The primary objective is to evaluate the safety, tolerability, and determine the recommended phase 2 dose and/or maximum tolerated dose of tarlatamab in combination with PD-L1 inhibition with or without chemotherapy. Secondary endpoints are objective response rate, duration of response, disease control, progression-free survival, overall survival, and pharmacokinetics

Profile of pembrolizumab in the treatment of head and neck squamous cell carcinoma: design development and place in therapy

Sulsal Haque,1,2 Mahender Yellu,1,2 Jaskirat Randhawa,1,2 Nooshin Hashemi-Sadraei1,2 1Division of Hematology/Oncology, Department of Medicine, University of Cincinnati, 2University of Cincinnati Cancer Institute, Cincinnati, OH, USA Abstract: Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide, and despite advances in cytotoxic, surgical and radiation techniques, outcomes are still poor in those with both locally advanced and metastatic diseases. The need for development of better therapeutics along with a greater understanding of the relationship between the immune system and malignancies has led to a new therapeutic modality, immune modulators, particularly checkpoint inhibitors in HNSCC. It is now well recognized that HNSCC circumvents crucial pathways utilized by the immune system to escape surveillance. These hijacked pathways include impairing tumor antigen presentation machinery and co-opting checkpoint receptors. This understanding has led to the development of monoclonal antibodies targeting checkpoint receptors and has resulted in promising outcomes in HNSCC. This article describes the mechanisms that HNSCC utilizes to escape immune surveillance, clinical impact of checkpoint inhibitors (with a focus on pembrolizumab), ongoing studies, and future directions. Keywords: pembrolizumab, head and neck cancer, MK-3475, immunotherap

Combined Radiation and PD-L1 Blockade Improved Tumor Control in Mouse Head and Neck Squamous Cell Carcinoma (HNSCC)

Purpose/Objective(s): Expression of the negative immune regulatory molecule, programmed death-ligand 1 (PD-L1) by tumor cells is associated with T cell dysfunction, attenuated antitumor immune responses, and poor clinical outcomes. Blocking the interaction between PD-L1 and its receptor, programmed death-1 (PD-1), expressed on activated CD8+ cytotoxic T lymphocytes (CTLs) enhances antitumor activity. Radiation induces cell death and is known to result in the release of tumor-associated antigens capable of triggering antitumor responses as well as enhancing antigen presentation. Radiation therapy (RT) is a commonly used treatment for locally advanced or recurrent HNSCC. In the current study, we examined the effect of radiation on major histocompatibility complex class I (MHC-I) and PD-L1 expression on HNSCC cell lines, and whether the combination of RT and PD-L1 blockade will improve tumor control

Combined radiation and PD-L1 blockade improved tumor control in mouse head and neck Squamous Cell Carcinoma (HNSCC)

Purpose/Objective(s): Expression of the negative immune regulatory molecule, programmed death-ligand 1 (PD-L1) by tumor cells is associated with T cell dysfunction, attenuated antitumor immune responses, and poor clinical outcomes. Blocking the interaction between PD-L1 and its receptor, programmed death-1 (PD-1), expressed on activated CD8+ cytotoxic T lymphocytes (CTLs) enhances antitumor activity. Radiation induces cell death and is known to result in the release of tumor-associated antigens capable of triggering antitumor responses as well as enhancing antigen presentation. Radiation therapy (RT) is a commonly used treatment for locally advanced or recurrent HNSCC. In the current study, we examined the effect of radiation on major histocompatibility complex class I (MHC-I) and PD-L1 expression on HNSCC cell lines, and whether the combination of RT and PD-L1 blockade will improve tumor control