Siltuximab (1) – Sylvant®

• Clinical trials
  • The assessment of the extent of the additional benefit of siltuximab is based on the MCD2001 study.
  • The MCD2001 study is a randomised, placebo-controlled, multicentre, double-blind Phase II trial, which tested the efficacy and safety of treatment with siltuximab plus best supportive care (BSC) versus placebo plus BSC in patients with MCD.

Treatment of multicentric Castleman’s disease (MCD) in adult patients who are HIV-negative and HHV-8-negative

• mortality
  • In the study, ‘overall survival’ was assessed as a secondary endpoint.
  • At the time of the clinical cut-off, the median duration of follow-up was 422 days. The median overall survival had not yet been reached in either the placebo group or the siltuximab group. Two deaths (3.8%) occurred in the siltuximab arm versus four (15.4%) in the control arm. The results were not statistically significant.
• Morbidity – Sustained tumour and symptom response (complete response (CR) and partial response (PR))
  • The primary endpoint ‘sustained response of tumour and symptoms (complete response (CR) + partial response (PR))’ is a composite endpoint comprising the two endpoints ‘tumour response’ and ‘sustained remission of symptoms’.
  • 18 patients (34.0 %) in the siltuximab arm achieved the primary endpoint of a tumour and symptom response lasting at least 18 weeks. In the placebo arm, no patient achieved this endpoint. The difference was statistically significant in the a priori planned statistical analysis using the Cochran-Mantel-Haenszel test (absolute difference: 34.0%; 95% CI: [11.1; 54.8]; p = 0.0012).
  • The results for the primary endpoint are mainly attributable to partial responses. Of the 18 patients in the siltuximab arm, one patient achieved a complete response (CR) and 17 patients achieved a partial response (PR) in terms of tumour and symptoms (relative risk (RR): 17.50; 95% CI: [1.09; 280.09]; p = 0.0400).
  • Complete response in terms of both tumour and symptoms is clinically relevant. However, there is uncertainty regarding the clinical relevance of partial response, as the definition of the combined endpoint merely requires no worsening of symptoms alongside a tumour reduction of at least 50 per cent.
  • At the time of data analysis, the median duration of durable response in the siltuximab arm was 383 days.
  • For the endpoint ‘sustained response of tumour and symptoms’, siltuximab therefore showed an advantage over placebo. However, given that the assessment tool was not validated, no conclusions can be drawn regarding the extent of the additional benefit with respect to the endpoint ‘sustained response of tumour and symptoms’.
• quality of life
  • Changes in quality of life were assessed using both summary scales (Physical Component Scale, PCS, and Mental Component Scale, MCS) of the generic Medical Outcomes Study 36-Item Short Form Health Survey (SF-36).
  • The treatment effect is not statistically significant for the physical summary scale. The improvement in the mental health domain is statistically significant in favour of siltuximab: here, an improvement of more than 5 points was observed in 68.0% of patients treated with siltuximab, compared with 34.6% of those treated with placebo. The median time to improvement was 104 days in the siltuximab group and 302 days in the placebo group (HR: 2.41; 95% CI: [1.142; 5.091]; p = 0.0173). Given the magnitude of the effect, a clinically relevant difference can be assumed. The treatment benefit of siltuximab is assessed as minor.
  • With regard to the quality of life endpoint, there is a minor additional benefit in terms of improving psychological quality of life.
• Side effects
  • The median duration of treatment during the blinded phase of the study was 152 days in the placebo group and 375 days in the siltuximab group.
  • The proportion of patients with at least one AE was 100% in the siltuximab arm and 96.2% in the placebo arm. The most commonly reported AEs in the siltuximab group were pruritus (42%), upper respiratory tract infections (36%), maculopapular rash and fatigue (34% each), and peripheral oedema (32%).
  • The proportion of patients with at least one AE of CTCAE grade 3 or higher was 54% in the placebo arm and 47% in the siltuximab arm.
  • Serious AEs (SAEs) occurred in 19% of patients in the placebo arm and in 23% of patients in the siltuximab arm.
  • The post-hoc analysis of the results for the various safety endpoints revealed no difference in treatment outcomes between the treatment arms.
  • AE of particular interest include infusion reactions due to the study medication, infections, thrombocytopenia and neutropenia. Here, siltuximab shows a numerical disadvantage. For infections and parasitic diseases, the difference between treatments is statistically significant (RR: 1.91; 95% CI: [1.09; 3.35]; p = 0.024).
  • With regard to the interpretation of the results concerning side effects, there are uncertainties on the one hand due to the double counting of outcomes in both morbidity endpoints and safety endpoints, as symptoms of the disease—which are also included in the efficacy endpoints (‘sustained tumour and symptom response’ and ‘sustained symptom remission’)—may have been recorded as AEs to a significant extent. On the other hand, given the difference in median duration of treatment and the associated longer duration of exposure to the study medication in the siltuximab group, a bias in the results must be assumed.
  • Taken together, the available results do not allow any conclusions to be drawn regarding the extent of the additional benefit with regard to side effects.

Courtesy translation only, please refer to the German original.