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

Jun 5, 2020

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. 1Thus, 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). 2The 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 XIAPgene levels
  • Patient baseline characteristics are shown below in Table 1

Table 1 . Patient baseline characteristics from the LCL161 phase II trial 2

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, %

JAK2V617F

CALR

MPLW515L

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 cIAP1reduction was induced and sustained cIAP1reduction occurred in all long-term responders
    • High baseline levels and/or an increase in XIAPlevels 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 trial 2

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 trial 2

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.

  1. Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol.2018;97(3):435-441. DOI: 1007/s00277-017-3194-4
  2. Pemmaraju N, Carter BZ, Kantarjian HM, et al. Final results of phase 2 clinical trial of LCL161, a novel oral SMAC mimetic/IAP antagonist, for patients with intermediate to high risk myelofibrosis. Oral Abstract #634. 61st American Society of Hematology (ASH) Annual Meeting & Exposition; Nov 13, 2019; Orlando, US.