A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer

Abstract

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n = 21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n = 21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥ 2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triplenegative breast cancer patients (n = 5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

“…In addition to the aforementioned IDO1 inhibitors, some other small molecules or vaccines have fared clinical development, including LY3381916, MK-7162, IO102 and KHK2455, alone or combined with ICI. For example, LY3381916 is a highly selective and potent inhibitor of IDO1 that was evaluated alone or combined with a PD-L1 blocker in patients with advanced or metastatic cancer (102). No clear clinical activity was detected, thus warranting further studies.…”

Structure and Plasticity of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…6,7 Clinical trials with apo-IDO1 inhibitors, having a different inhibition mechanism from epacadostat, are ongoing. 4,8,9 In addition to its enzymatic activity, IDO1 also displays a signaling activity mediated by two immunoreceptor tyrosinebased inhibitory motifs and a post-transcriptional regulatory site. 2 IDO1's interaction sites with Src homology 2 domain phosphatases (SHPs), 10 phosphoinositide 3-kinases (PI3Ks), 11 and suppressor of cytokine signaling 3 (SOCS3) 12 are all localized in the small domain and are distinct from the enzymatic active site in the large domain (Figure 1A).…”

“…As a key regulator of immune responses, IDO1 is an important therapeutic target for diseases that involve pathological immune escape, such as cancer. , Numerous small-molecule IDO1 inhibitors have been published since the discovery of the implication of IDO1 in tumoral immune resistance, and several compounds entered clinical evaluation. , However, despite compelling preclinical and early clinical data, a phase 3 clinical trial of the IDO1 inhibitor epacadostat in combination with pembrolizumab (ECHO-301) failed to increase the overall and progression-free survival when compared to pembrolizumab alone . Potential reasons for the negative outcome of this clinical trial and possible solutions have been suggested, for example, intratumoral kynurenine level monitoring in combination with the use of more potent and more selective IDO1 inhibitors or dual IDO1–tryptophan 2,3-dioxygenase (TDO) inhibitors. , Clinical trials with apo-IDO1 inhibitors, having a different inhibition mechanism from epacadostat, are ongoing. ,, …”

Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy

“…We speculate that this might be related to PD-1/PD-L1 inhibitor resistance in some patients with NSCLC ( Lei et al, 2020 ). This suggests that inhibiting the tryptophan-kynurenine pathway through the administration of indoleamine-2,3-dioxygenase inhibitors may benefit NSCLC patients who are resistant to PD-1/PD-L1 inhibitors ( Kotecki et al, 2021 ).…”