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.

Conflict of interest statement

Conflict-of-interest disclosure: N.P. has been a consultant to and received honoraria from Celgene, Stemline, Incyte Novartis, MustangBio, Roche Diagnostics, LFB, and Pacylex and has received research funding and clinical trial support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and the SagerStrong Foundation.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

LCL161 in MF. (A) Swimmer plot for all responding patients. The legend embedded in the graph indicates the markers of CI and other responses. Disease stages per IPSS: Int 2, intermediate-risk 2; high, high-risk MF. (B) Table of characteristics and responses. All responses are per IWG-MRT 2013 response criteria for MF. TSS, total symptom score; Hgb, hemoglobin (g/dL); spln, spleen; CR (cyto), complete remission cytogenetics. Prior RX: Ara, Aransep; Thal, thalidomide; RUX, ruxolitinib; Pomalid, pomalidomide; DAC, decitabine; IA, idarubicin+ARA-C; alloSCT, allogeneic stem cell transplant; ACE-011, sotatercept. IFN, interferon; PEG IFN, pegylated interferon; Revlimid, lenalidomide; ANAG, anagrelide; AZA, azacytidine. WBC, white blood cell count (×103/μL); PLT, platelet (×103/μL); RespDUR (m), response duration in months, TxDUR (m), treatment duration in months (C) Spleen changed in size shown by waterfall plot. Each bar represents an individual patient response. All spleen size measurements in this study were performed by physical examination (palpation). Bsln, baseline spleen size. (D) LCL161 in MF anemia responders (n = 6). All responses are per IWG-MRT 2013 criteria for MF.

Figure 1.

LCL161 in MF. (A) Swimmer plot for all responding patients. The legend embedded in the graph indicates the markers of CI and other responses. Disease stages per IPSS: Int 2, intermediate-risk 2; high, high-risk MF. (B) Table of characteristics and responses. All responses are per IWG-MRT 2013 response criteria for MF. TSS, total symptom score; Hgb, hemoglobin (g/dL); spln, spleen; CR (cyto), complete remission cytogenetics. Prior RX: Ara, Aransep; Thal, thalidomide; RUX, ruxolitinib; Pomalid, pomalidomide; DAC, decitabine; IA, idarubicin+ARA-C; alloSCT, allogeneic stem cell transplant; ACE-011, sotatercept. IFN, interferon; PEG IFN, pegylated interferon; Revlimid, lenalidomide; ANAG, anagrelide; AZA, azacytidine. WBC, white blood cell count (×103/μL); PLT, platelet (×103/μL); RespDUR (m), response duration in months, TxDUR (m), treatment duration in months (C) Spleen changed in size shown by waterfall plot. Each bar represents an individual patient response. All spleen size measurements in this study were performed by physical examination (palpation). Bsln, baseline spleen size. (D) LCL161 in MF anemia responders (n = 6). All responses are per IWG-MRT 2013 criteria for MF.

Figure 2.

OS. Kaplan-Meier estimator curve for OS. All 50 patients treated are included. Median OS was 34 months (range, 2.2-60.1+ months).

Figure 3.

cIAP1, cIAP2, and XIAP expression during LCL161 treatment for MF. IAP protein expression. Samples were collected on C1D1, C2D1, and C3D1. Protein levels of cIAP1, cIAP2, and XIAP were determined by Western blot, quantified using the Odyssey software, and expressed as levels related to those in baseline (C1D1) or to those in OCI-AML3 cells (as a control). (A) IAP levels in samples from responders (≥ 2 years). (B) IAP levels in blood samples from responding, then relapsed patient samples. (C) IAP levels in samples from nonresponders. (D) IAP levels in baseline C1D1 samples. Differences between groups were assessed with the Student t test. *P < 0.05; **P < 0.01; ***P < 0.001; *****P < 0.0001.