Final phase II results of the SMAC mimetic LCL161 for intermediate/high-risk myelofibrosis

Patients with myelofibrosis (MF) who are ineligible, intolerant, or fail to respond to Janus kinase (JAK) inhibition have limited treatment options and poor outcomes, with a median overall survival of 13 months.¹ Thus, there is a great unmet medical need for the development of alternative treatments for this patient subset.

The second mitochondrial-derived activator of caspases (SMAC) mimetic LCL161 has shown, in preclinical studies, to induce apoptosis in MF cells by binding to the cellular inhibitor of apoptosis protein-1 (cIAP1) and the X-linked inhibitor of apoptosis protein (XIAP).² The efficacy and safety of the LCL161 was assessed in patients with relapsed or refractory MF of high/intermediate risk in a phase II trial (NCT02098161), and results were presented during the 61st American Society of Hematology  Annual Meeting & Exposition (ASH 2019) by Pemmaraju Naveen. This article is based on data presented at the ASH meeting and may supersede the data in the published abstract.

Study design

• Investigator-initiated, single-center, open-label, phase II trial
• Patients with primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF of intermediate or high risk who were ineligible, intolerant, or failing to respond to JAK inhibitors
• N = 50 patients received a starting dose of 1,500 mg of oral LCL161, once weekly, with two subsequent dose reductions (DL1: 1,200 mg and DL2: 900 mg)
• Treatment cycles lasted 28 days and were repeated until disease progression or unacceptable toxicity
• Primary endpoint: Overall response rate (ORR) based on the International Working Group-Myeloproliferative Neoplasms Research and Treatment 2013 criteria
• Secondary and exploratory endpoints: Time to response, response duration, safety, symptom burden, mutational profiling with cIAP1/2 and XIAP gene levels
• Patient baseline characteristics are shown below in Table 1

Table 1. Patient baseline characteristics from the LCL161 phase II trial²

Results

• The final efficacy results from the trial are shown in Table 2
• At a median follow-up of 22.7 months (range, 1.5–55.2+), the median overall survival was not reached, and a median number of five treatment cycles were completed
• From the six patients that achieved clinical improvement of anemia, four showed improvement in hemoglobin levels and the other two reached transfusion independence
• Five out of 18 (28%) patients currently remain on the study and 80% of them have ongoing responses. Eight patients achieved a response for longer than 1 year
• To date, 39 out of 50 patients (78%) went off the study due to the following:
  • Lack of response (n = 16)
  • Disease progression/relapse (n = 10)
  • Patient choice (n = 5)
  • Concomitant diseases (n = 3)
  • Proceeding to allogeneic stem cell transplant (n = 2)
  • Toxicity (n = 2)
  • Achieving symptom clinical improvement but nothing else (n = 1)
• Correlation of efficacy and molecular profiling:
  • In all responding patients, on target cIAP1 reduction was induced and sustained cIAP1 reduction occurred in all long-term responders
  • High baseline levels and/or an increase in XIAP levels correlated with disease progression and loss of response, indicating a possible escape mechanism for LCL161

Table 2. Key efficacy responses from the LCL161 phase II trial²

Safety

• A table with all the adverse events observed during the LCL161 trial are shown in Table 3
• Dose reductions occurred in 18/50 patients (36%), with the most common reason being Grade 2 fatigue (n = 10)
  • Five patients received two dose reductions; two of these still remain on the study at 900 mg, once weekly
  • Two patients discontinued treatment due to toxicity (Grade 2 fatigue, Grade 3 syncope)

Table 3. Toxicities reported in the LCL161 phase II trial²

Conclusion

The final results of this phase II trial show that the SMAC mimetic LCL161 led to an ORR of 30% in patients with relapsed/refractory MF of intermediate/high risk. The median overall survival was not reached at a median follow-up of approximately 22 months. It is planned to investigate LCL161 in combination with other targeted therapies, such as ruxolitinib, to further enhance efficacy in patients with MF.