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

ASXL1, additional sex combs-like 1; CALR, calreticulin; DNMT3A, DNA-methyltransferase 3 alpha; EZH2, enhancer of zeste homolog 2; IMiD, immunomodulatory drug; IPSS, International Prognostic Scoring System; JAK, Janus kinase; MPL, myeloproliferative leukemia; RAS, rat sarcoma; SCT, stem cell transplant; TET2, ten-eleven translocation 2; TP53, tumor protein p53
Patient characteristic (N = 50)
Median age, years (range)	72 (56–85)
Males, %	56
Median hemoglobin levels, g/dL (range)	8.7 (4.4–12)
Median leukocytes, K/μL (range)	5.9 (1.1–38)
Median platelets, K/μL (range)	52 (6–1,365)
Spleen size, cm (range) [n = 30]	12 (1–30)
Prior therapies, % ≥ 2 prior treatments Prior JAK inhibitor Prior IMiD® Prior SCT	66 56 24 4
IPSS at baseline, % Intermediate 1 risk Intermediate 2 risk High risk	4 22 74
Molecular mutation, % JAK2 V617F CALR MPL W515L ASXL1 TET2 DNMT3A RAS EZH2 TP53	64 12 12 28 15 11 9 9 2
Cytogenetics, % Diploid Unfavorable Insufficient	34 18 8

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

ORR, overall response rate *Response criteria based on the International Working Group-Myeloproliferative Neoplasms Research and Treatment (2013); all responses must have lasted for ≥ 12 weeks to qualify †Results at a median follow-up of 22.7 months (range, 1.5–55.2+)
Efficacy response (N = 50)*
ORR, n (%)	15 (30)
Symptom clinical improvement, n (%)	11 (22)
Anemia clinical improvement, n (%) Median time to anemia response, months (range) Median anemia response duration, months (range)	6 (12) 3.1 (0.9–9.1) 8.4 (5.5–28.6)
Spleen clinical improvement	1
Cytogenetic remission	1
Median overall survival†	Not reached
Median treatment cycles received†, n (range)	5 (1–61+)

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

TEAEs, treatment-emergent adverse events
Adverse event	%
Non-hematological adverse events, Grade 1–2
Nausea/vomiting Fatigue Dizziness/vertigo Pruritis Diarrhea Pain Skin eruption/rash Fever/flu-like syndrome	76 46 30 24 26 24 24 38
Non-hematological TEAEs, Grade 3–4
Syncope Nausea/vomiting	4 2
Hematological TEAEs, Grade 3–4
Thrombocytopenia Anemia	6 4

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.