Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis

Abstract

Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

“…The unequivocal presence of cIAPs in the CD137 signalosome prompted us to ascertain the actual involvement of cIAPs in CD137 function. SMCs target cIAP1 and cIAP2 causing their rapid degradation ( 46 ) and as drugs are currently undergoing clinical trials for malignant indications ( 57 , 58 ). To explore the extent of cIAP involvement in the signaling pathway and function of CD137, we used BV6, birinapant, and xevinapant as three highly active SMCs ( 59 , 60 ) and we also used transfections of DN mutants of cIAP1 (H588A),cIAP2 (H574A), and TRAF2 ΔRING (a truncated form of TRAF2 that lacks the RING domain) ( 38 ).…”

Targeting regulated cell death pathways in acute myeloid leukemia

“…ASTX660/Tolinapant is a dual antagonist of XIAP and cIAP is currently under investigation in phase 1/2 studies in solid tumors and in combination with hypomethylating agents in AML [ 105 , 106 ] . LCL161, an oral SMAC mimetic, has been tested in patients with myelofibrosis and showed a 30% objective response rate in a recently published phase 2 trial [ Table 2 ] [ 107 ] .…”

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer

“…These SMAC mimetics were found to enhance the sensitivity of NSCLC cells to multiple chemotherapeutic agents [ 101 , 103 ]. In addition, clinical phase I and II trials targeting IAPs using SMAC mimetics are underway [ 104 , 105 , 106 ].…”