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Phase I/II study of the FLT3 inhibitor pexidartinib in patients with relapsed/refractory AML with FLT3-ITD mutations

Jun 2, 2020

FMS-like tyrosine kinase 3 ( FLT3) mutations, such as internal tandem duplication (ITD) and point mutations in the FLT3 tyrosine kinase domain (TKD), are common in acute myeloid leukemia (AML).

Tyrosine kinase inhibitors (TKIs) of FLT3 that demonstrate activity in patients with FLT3mutations include the following:

  •  Midostaurin, a multitargeted inhibitor, approved for the treatment of patients with newly diagnosed FLT3-mutant AML
  •   Quizartiniband gilteritinib, next-generation FLT3 inhibitors, showing high response rates as monotherapy in relapsed/refractory (R/R) patients with FLT3mutations
    • Quizartiniband gilteritinibboth confer a survival benefit, compared with salvage chemotherapy, in patients with R/R FLT3-mutant AML
    • Gilteritinib is approved for the treatment of patients with R/R FLT3-mutant AML

Unfortunately, because of the development of therapeutic resistance, survival in patients with R/R FLT3-mutant AML remains poor. Currently, there are limited options for the treatment of patients with FLT3 TKI resistance, commonly due to mutations in the FLT3 TKD at the kinase gatekeeper residue F691 (F691L mutation), which interfere with the binding capacity of TKIs.

Pexidartinib is a small-molecule kinase inhibitor with selective activity against colony-stimulating factor 1 receptor (CSF1R), proto-oncogene receptor  tyrosine kinase, and FLT3-ITD. Pexidartinib is able to maintain binding to FLT3 with a F691L mutation, and preclinical studies have shown that pexidartinib is active in cells expressing FLT3-ITD/F691L mutations. In this phase I/II study, published in Blood Advances, Catherine Smithand colleagues evaluated the safety and efficacy of pexidartinib in patients with R/R AML with FLT3-ITD mutations.

Study design and patient characteristics

This open-label, phase I/II trial enrolled 90 patients with R/R FLT3-ITD +AML and consisted of a dose-escalation part (Part 1; n = 34) followed by a dose-expansion cohort (Part 2; n = 56). The primary objective of the dose-escalation part was to determine the maximum tolerated dose (MTD) and recommend a phase 2 dose (RP2D) of pexidartinib to treat patients in a subsequent dose-expansion cohort. The Part 2 objective was to determine the overall response rate at the RP2D:

  • Primary efficacy endpoint: Rate of composite complete remission (CRc), including complete remission (CR), CR with incomplete recovery (CRi), and CR with incomplete platelet recovery (CRp), plus the percentage of patients who were successfully bridged to transplantation
  • Secondary endpoints: Partial remission (PR), duration of remission, overall survival (OS), and progression-free survival (PFS)

Pexidartinib was given orally twice daily from Day 1 to Day 28 of each 28-day cycle. The design of the study is reported in Figure 1. Baseline characteristics of patients enrolled in the study are shown in Table 1.

Figure 1. Study design 1

Table 1. Patient characteristics

AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; MDS, myelodysplastic syndrome


Characteristic

Part 1

(n = 34)

Part 2

(n = 56)

Age, years (range)

60.6 (24–82)

55.9 (22–83)

Sex, n (%)

Male

Female

 

13 (38)

21 (62)

 

33 (59)

23 (41)

ECOG performance status, n (%)

Fully active (0)

Restricted (1)

Ambulatory (2)

 

6 (18)

17 (50)

11 (32)

 

9 (16)

33 (59)

14 (25)

AML category at diagnosis, n (%)

De novo

Secondary to MDS

Secondary to chemotherapy for another cancer

Unknown

 

26 (76)

4 (12)

2 (6)

 

2 (6)

 

44 (79)

2 (4)

4 (7)

 

6 (11)

FLT3-ITD +at diagnosis, n (%)

Yes

No

Unknown

 

30 (88)

2 (6)

2 (6)

 

45 (80)

4 (7)

7 (13)

Prior FLT3 inhibitor therapy, n (%)

14 (41)

12 (21)

Prior allogeneic transplantation, n (%)

Yes

No

Unknown

 

7 (21)

27 (79)

0

 

21 (38)

34 (61)

1 (2)

Prior AML therapies, median (range)

4 (2–12)

4 (1–10)

Results

Data cutoff date was January 20, 2015.

Safety

In the dose-escalation part, eight different doses of pexidartinib were investigated ( Figure 1), and no dose-limiting toxicities related to study treatment were observed.

The most frequent treatment-emergent adverse events (TEAEs) occurring in ≥ 20% of patients are reported in Table 2. Twelve patients (13%) died during the study (Part 1, n = 3; Part 2, n = 9) because of sepsis (n = 5), pneumonia (n = 2), pneumonia aspiration (n = 1), respiratory failure (n = 1), cardiac arrest (n = 1), cytokine release syndrome (differentiation syndrome; n = 1), and cerebral hemorrhage (n = 1). Only the death due Grade 5 cytokine release syndrome, which occurred in Part 2, was considered related to the treatment.

Table 2. TEAEs occurring in ≥ 20% of patients 1

TEAE, treatment-emergent adverse event

TEAE, n (%)

Grade 1–2

Grade ≥ 3

All grades

Diarrhea

44 (49)

1 (1)

45 (50)

Fatigue

33 (37)

9 (10)

42 (47)

Nausea

40 (44)

1 (1)

41 (46)

Febrile neutropenia

0 (0)

38 (42)

38 (42)

Decreased appetite

31 (34)

2 (2)

33 (37)

Vomiting

32 (36)

1 (1)

33 (37)

Cough

26 (29)

0 (0)

26 (29)

Anemia

9 (10)

15 (17)

24 (27)

Hypokalemia

16 (18)

6 (7)

22 (24)

Aspartate aminotransferase increased

14 (16)

5 (6)

19 (21)

Dyspnea

15 (17)

3 (3)

18 (20)

Pharmacokinetic data indicated that at pexidartinib doses ˃ 3,000 mg, plasma exposure levels did not increase. Therefore, the dose of 3,000 mg was chosen as the R2PD and used in the dose expansion part of the study.

Efficacy

For all treated patients (N = 90), the overall response rate (≥ PR) was 21% (n = 19), and the overall composite CRc ( CRc consisting of CR, CRi, and CRp) rate was 11% (n = 10). The best responses observed in Part 1 and Part 2 of the study are reported in Figure 2.

Six patients underwent hematopoietic stem cell transplantation (HSCT; three after response:  PR, n = 1; CRi, n = 1; CRp, n = 1):

  • Three received pexidartinib maintenance after HSCT
    • Two discontinued maintenance (one relapsed 6 months after HSCT, and one relapsed 2 years after HSCT)
    • One patient was still on treatment without relapse at the cutoff date
  • Of the remaining three
    • Two relapsed 100 days post-HSCT
    • One was lost to follow-up

Figure 2. Response rates in APart 1 and BPart 2 of the study 1

CR, complete remission; CRi, CR with incomplete recovery; CRp, CR with incomplete platelet recovery; PR, partial remission

The median duration of response, PFS, and OS stratified for response and pexidartinib dose are reported in Table 3. In responders (≥ PR) vsnon-responders, the median PFS was extended by 98 days and the median OS by 171 days. No significant differences in PFS and OS were found between patients treated at doses < 3,000 mg and patients treated at doses ≥ 3,000 mg.

Table 3. Secondary endpoints 1

CR, complete remission; CRc, composite CR; CRi, CR with incomplete recovery; CRp, CR with incomplete platelet recovery; OS, overall survival; PFS, progression-free survival; PR, partial remission

 

Median duration of response

Median PFS

Median OS

Median time to best response

Part 1, days

74

57

91

30

Part 2, days

76

48

112

30

Responders (≥ PR) vsnon-responders, days

133 vs35

250 vs79

Complete responders (CRi, CRp, or CR), days

265

CRc (n = 9), days

212

Pexidartinib < 3,000 vs≥ 3,000 mg

57 vs52

92 vs96

In patients pretreated with TKI, the response rate was lower than in FLT3 TKI-naïve patients: 14.8% (4/27 patients; CR, n = 1; PR, n = 3) vs23.8% (15/63 patients; CR, n = 1; CRi, n = 6; CRp, n = 2; PR, n = 6), respectively.

The potential clinical activity of pexidartinib in patients with FLT3F691L mutations was evaluated in four patients with F691L mutations at the time of drug initiation. Of these patients, two were treated at a dose of 1,000 mg per day: one at 1,200 mg and one at 2,000 mg. Only the patient treated at the dose of 2,000 mg achieved a CRi.

Conclusion

This study shows that pexidartinib is well tolerated in heavily pretreated patients with R/R FLT3-ITD +AML. Survival benefits were observed in responders (≥ PR) vsnon-responders, with a median PFS extended by 98 days and median OS by 171 days.

Further studies are required to determine the clinical activity of pexidartinib in patients with FLT3F691L mutations because of the small number of patients with F691L mutations in this study.

Expert Opinion

This phase I/II trial of the novel oral FLT3 inhibitor, pexidaritinib, in patients with relapsed/refractory FLT3 ITD mutant AML was disappointing with much lower response rates (21%) than that achieved with other second generation FLT3 inhibitors (gilteritinib, quizartinib) in similar patients. This may have been due to decreased potency of this agent with doses of ≥3000 mg required for maximal FLT3 inhibitor. Nevertheless pexidaritinib was overall well tolerated and its potential activity against the FLT3 F691L gatekeeper mutation conferring resistance to all other known inhibitors suggests it may be useful for patients whose disease has progressed following other FLT3 inhibitor therapy such as gilteritinib.

  1. Smith CC, Levis MJ, Frankfurt O, et al. A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia. Blood Adv.2020;4(8):1711-1721. DOI: 1182/bloodadvances.2020001449