Letermovir (1) – Prevymis®

• Clinical trials
  • MK-8228-001 is a Phase III, placebo-controlled, randomised, double-blind trial conducted to support marketing authorisation, designed to investigate the efficacy and safety of letermovir.

Letermovir for the prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of allogeneic haematopoietic stem cell transplantation

• mortality
  • At week 24 post-transplant, a statistically significant advantage of letermovir (12.3%) over placebo (18.8%) was observed in the time-to-event analysis of all-cause mortality (HR = 0.62 [0.39; 0.98]; p = 0.042).
  • At the 48-week analysis point, the difference between the study arms was no longer statistically significant (HR = 0.79 [0.55; 1.14]; p = 0.214).
  • These results already take into account the post-study analyses; however, the survival status could not be determined for 18 patients.
  • Overall, an advantage in overall survival is observed. However, this cannot be quantified due to the lack of statistical significance at 48 weeks and the 18 patients with unknown survival status.
  • The endpoint ‘CMV-associated mortality’, additionally presented by the pharmaceutical manufacturer, cannot be taken into account for the benefit assessment, as it remains unclear to what extent the operationalisation used actually reflects the association between infection and death.
• Morbidity – Clinically significant CMV infection
  • The endpoint ‘clinically significant CMV infection’ is the primary endpoint of the study. It comprises the endpoints ‘CMV organ disease’ and ‘initiation of pre-emptive therapy’.
  • The occurrence of CMV organ disease is of direct relevance to patients. The operationalisation via diagnosis and assessment by a blinded committee is transparent. At none of the evaluation time points (14, 24 and 48 weeks) was there a statistically significant difference in the incidence rate between the two study arms.
  • At week 48, 8 out of 325 patients (2.5%) in the letermovir group and 6 out of 170 patients (3.5%) in the placebo group met the criteria for the endpoint (p = 0.438).
  • The statistically significant result for the endpoint ‘initiation of pre-emptive therapy’ also leads to statistical significance for the composite endpoint ‘clinically significant CMV infection’ at the 14- and 24-week assessment time points.
  • For the endpoint ‘initiation of pre-emptive therapy’, the statistically significant result, when taking the extent of the effect into account, suggests a clear improvement in treatment-related benefit with letermovir.
• Quality of life – FACT-BMT
  • The FACT-BMT instrument for assessing quality of life comprises the generic questionnaire ‘Functional Assessment of Cancer Therapy – General’ (FACT-G) and the 12-item ‘Bone Marrow Transplantation Subscale’ (BMTS).
  • The total score is sufficiently validated and the operationalisation is transparent.
  • Response rates of > 70% were not achieved for either treatment arm at any of the follow-up visits. Consequently, there are insufficient data available to evaluate the results.
• Side effects
  • Data from week 16 post-transplantation in the ASaT population were used to assess adverse events.
  • The proportion of patients with AEs, severe AEs and SAE was comparable between the treatment arms; however, when analysing therapy discontinuations due to adverse events, a significant difference was observed in favour of letermovir (19.6% vs. 51.6%; HR = 0.33 [0.24; 0.45]; p < 0.001).
  • The inclusion of the endpoints CMV viremia/infection, GvHD and opportunistic bacterial and fungal infections within the morbidity category already ensures that differences between the groups are captured, thereby obviating the need for an additional analysis under the heading of side effects.
  • When this analysis method was applied, the proportion of patients with AEs and SAEs was also comparable between the treatment arms; however, there was no longer a significant difference in therapy discontinuations due to AEs.
  • Based on this supplementary analysis, there is therefore no clear advantage or disadvantage of letermovir in terms of side effects.
  • Even when specific adverse events are considered, there are no significant differences in the hazard ratio, except for SAE in the system organ class ‘Renal and urinary disorders’, where there is an advantage in favour of letermovir (2.7% vs. 5.7%; HR = 0.39 [0.17; 0.92]; p = 0.033; supplementary analysis: 2.4% vs. 5.7%; HR = 0.35 [0.14; 0.85]; p = 0.020).
  • A clear advantage for letermovir cannot be inferred from this single result given the small sample size.
• Overall assessment
  • The additional benefit of letermovir was assessed on the basis of the results of the registration trial MK-8228-001.
  • Advantages of letermovir over placebo were observed in terms of overall mortality and morbidity (endpoints ‘clinically significant CMV infection’ and rehospitalisation).
  • No advantages for letermovir were observed for other morbidity endpoints or for side effects.
  • It was not possible to evaluate the results on health-related quality of life due to insufficient questionnaire response rates.
  • In the overall assessment, it must be borne in mind that the extent of the advantages is assessed differently: whilst the advantage with regard to the endpoint ‘clinically significant CMV infection’ can be classified as considerable when considered in isolation, only a minor additional benefit can be assumed with regard to the advantages for ‘rehospitalisations’.
  • By contrast, the advantage relating to the endpoint of mortality cannot be quantified in terms of its magnitude.
  • If, when combining the advantages—which vary in extent—to form an overall assessment of the additional benefit, one takes into account that the endpoint of mortality is of particular importance for treatment in the present therapeutic indication, this data set justifies the conclusion that the extent of the additional benefit is non-quantifiable.

Courtesy translation only, please refer to the German original.