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iMCD: The spectrum of disease and clinical behaviour – Treatment

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Dr. James Cavet, Consultant Haematologist discusses the treatment of iMCD using SYLVANT®.

STUDY DESIGN & PATIENT CHARACTERISTICS

SYLVANT® (SILTUXIMAB) IS LICENSED FOR THE TREATMENT OF ADULT PATIENTS WITH
MCD WHO ARE HIV NEGATIVE AND HHV-8 NEGATIVE.1

Study Design

STUDY DESIGN

The efficacy and safety of SYLVANT® in symptomatic idiopathic Multicentric Castleman Disease (iMCD) was assessed in a Phase 2, multinational, randomised (2:1), double-blind, placebo-controlled study.1,2 This pivotal trial compared the percentage of patients who achieved a durable tumour and symptomatic response (primary endpoint) in SYLVANT® (+ best supportive care [BSC]) and placebo (+ BSC) treatment groups.1,2 Additional clinical and quality of life measures were included as secondary endpoints.

See Study Design

Patient Characteristics

PATIENT CHARACTERISTICS

In general, patient baseline characteristics (including histological subtype) were well balanced between the treatment groups (Table 4).1 However the SYLVANT® group included a lower proportion of males than the placebo group.

Table 4: Baseline characteristics3

SYLVANT®
(n=53) 		PLACEBO
(n=26)
Median age (range), years 47 (20–74) 48 (27–78)
Male, % 57 85
ECOG Score, %
0
1
2
42
45
13
38
62
0
Prior use of systemic therapies for MCD (including corticosteroid use), % 55 65
Concomitant corticosteroid use, % 25 35
Histological subtype, %
Hyaline vascular
Plasmacytic
Mixed subtype
34
25
42
31
19
50

EFFICACY RESULTS

RESULT HIGHTLIGHTS

Significantly more iMCD patients receiving SYLVANT® (+ BSC) achieved a durable tumour and symptomatic response
(primary endpoint) than patients receiving placebo (+ BSC)3

Result Highlights

The median duration of a durable tumour and symptomatic response with SYLVANT® (+BSC) was 383 days (range 232 – 676).3

Individual components of the primary endpoints were assessed as secondary endpoints. Significantly more patients receiving SYLVANT® (+BSC) vs those patients receiving placebo (+BSC) achieved a durable or complete symptomatic response (Figure 4). For the 30 patients who achieved a durable symptomatic response with SYLVANT® (+BSC), the median time to durable symptomatic response was 33 days (range 20-295).3 Time to durable symptomatic response was not evaluable for the placebo (+BSC) treatment arm. Time to durable symptomatic response was not evaluable for the placebo (+BSC) treatment arm.

In addition more patients receiving SYLVANT® (+BSC) achieved a partial or complete tumour response compared to those receiving placebo (+BSC)
(Figure 4).

Further analysis revealed that the overall response rate dropped significantly (P=0.0003) to 0% for the 16 SYLVANT®-treated patients who did not meet threshold criteria for the diagnosis of iMCD (Figure 5).4

Figure 4: Percentage of patients achieving primary and key secondary endpoints3

Figure 4: Percentage of patients achieving primary and key secondary endpoints

*  p < 0.005.
†  By independent review.

See Summary of key efficacy data

An open label, non-randomised Phase 2 extension study assessed the long-term safety and efficacy of SYLVANT® in 60 patients with MCD (41 were recruited from the pivotal study; 19 from an additional phase 1 study).1,5

After a median follow-up of 6 years, none of the 60 patients had died.

Figure 5: Percentage of patients meeting proposed major criteria who responded to therapy, based on number of proposed Minor Criteria4

Figure 5: Percentage of patients meeting proposed major criteria who responded to therapy, based on number of proposed Minor Criteria

Evaluation of response to therapy according to the NCT01024036 study’s primary end point (decrease in lymph node size as per modified Cheson criteria in the absence of symptom progression) for the 54 of 79 patients randomised to the SYLVANT® arm.4 n represents total number of patients treated with at least that number of Minor Criteria and ≥1 laboratory abnormality. Using Fisher’s exact test, those who met ≥2 Minor Criteria were significantly more likely to respond to SYLVANT® than those who did not meet 2 Minor Criteria (P=0.0003).4

 

References

  1. SYLVANT® EU Summary of Product Characteristics (Sept 2019).
  2. LLC Clinical Trial. A Study to Evaluate the Efficacy and Safety of CNTO328 Plus Best Supportive Care in Multicentric Castleman’s Disease 2018 [Available from: https://clinicaltrials.gov/ct2/show/NCT01024036?term=siltuximab&recrs=e&phase=1&draw=2&rank=3].
  3. Van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966-74.
  4. Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017; 129(12): 1646-1657.
  5. Van Rhee F, Casper C, Voorhees PM, Fayad LE, Gibson D, Kanhai K, et al. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials. Lancet Haematol. 2020;7(3):e209-e217.

EUSA Sylvant © 2021 EUSA Pharma      Date of prep: November 2021    GL-SIL-2100103

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