Phase I/II Trial of the MEK1/2 Inhibitor Trametinib (GSK1120212) in Relapsed/Refractory Myeloid Malignancies: Evidence of Activity in Patients with RAS Mutation-Positive Disease

Abstract

677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

Durable Disease Control with MEK Inhibition in a Patient with NRAS-mutated Atypical Chronic Myeloid Leukemia

“…Although we do not have information regarding the status of the patient’s bone marrow and the current allele burden of the NRAS-G12D mutation, his overall depth and duration of response strongly suggests that targeting the RAS-RAF-MEK-ERK may provide significant hematologic and clinical benefit to patients with aCML and perhaps other hematologic malignancies with NRAS mutations. Indeed, an ongoing Phase I/II clinical trial of trametinib has noted promising clinical activity in patients with RAS -mutated relapsed/refractory myeloid malignancies [ 9 ], and two Phase II clinical trials are underway to evaluate the safety and efficacy of trametinib treatment in combination with an AKT inhibitor for AML and multiple myeloma. When completed, the results of these studies may provide greater insight into the benefits of targeting MEK1/2 in hematologic malignancies.…”

Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent

“…Parallel siRNA and small molecule screens demonstrated the functional importance of the activated NRAS/Raf/MEK/ERK pathway in vitro. MEK inhibitors such as trametinib have shown activity in RAS-mutated AML; however, the overall response rate is only 28 %, indicating that a RAS mutation by itself is not sufficient to predict which patients will respond to therapy [ 14 ]. While trametinib monotherapy did not lead to CR in this patient, it did reduce peripheral blast counts and provided 6 months of disease control, allowing time to potentially coordinate a stem cell transplant.…”

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

“…[8][9][10][11][12][13] In RKO tumor xenograft models, AMG 232 had antitumor activity as monotherapy that was enhanced in combination with a MEK inhibitor. 10 Furthermore, phase 1 clinical studies have shown evidence of efficacy with MDM2 inhibitors and MEK inhibitors in AML, 14,15 suggesting that combination therapy may result in greater clinical activity. In clinical studies, increased blood levels of macrophage inhibitor cytokine-1 (MIC-1) has been used as a pharmacodynamic marker of treatment with other MDM2 inhibitors in patients with relapsed/refractory AML and in patients with other solid tumors, indicating on-target biological activity.…”