Polatuzumab Vedotin (4) – Polivy®

• Clinical trials
  • The assessment of the additional benefit of polatuzumab vedotin for the treatment of adults with previously untreated DLBCL is based on the results of the multicentre, double-blind, placebo-controlled, randomised POLARIX trial, which compared polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (Pola + R-CHP) against rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).

Adults with previously untreated diffuse large B-cell lymphoma (DLBCL)

• An additional benefit is not proven.
• Overall, there are no differences relevant to the benefit assessment of polatuzumab vedotin. The additional benefit of Pola + R-CHP compared with R-CHOP for the treatment of adults with previously untreated DLBCL is therefore not proven.
• mortality
  • In the POLARIX trial, the endpoint of overall survival was defined as the time from randomisation to death from any cause.
  • With regard to the endpoint of overall survival, no statistically significant difference was observed between Pola + R-CHP and R-CHOP.
  • The median overall survival had not been reached in either study arm at the data cut-off date of 15 June 2022.
• Morbidity – Failure of curative treatment (event-free survival, EFS)
  • EFS-EOT was defined as the time from randomisation to the first occurrence of any of the following events: death from any cause, progression or relapse, or failure to achieve complete remission (CR) by the end of treatment.
  • This effect was not reflected in the event rate, for which no statistically significant difference was observed between the treatment groups.
  • Overall, the present statistically significant difference in EFS-EOT is not considered sufficiently robust, given the minor size of the effect and the existing limitations, to establish with sufficient certainty an improvement in the therapeutic benefit of Pola + R-CHP in relation to the failure of a potential cure through the curative therapeutic approach under consideration.
• Morbidity – Recurrences (Disease-Free Survival, DFS)
  • DFS-EOT was defined as the time from a documented complete remission (CR) at the end of treatment until the occurrence of a relapse or death from any cause.
  • Only patients who had achieved CR at the end of therapy in the intervention or control arm were included in the DFS-EOT analyses. This comprises 381 out of 500 (76%) versus 364 out of 500 (73%) patients in the intervention versus control arm.
  • Consequently, this is an analysis population selected on the basis of study treatment as opposed to the ITT population, which constitutes a breach of randomisation.
  • The DFS-EOT is therefore not suitable for benefit assessment of polatuzumab vedotin. The occurrence of relapses is reflected through the operationalisation of the EFS-EOT endpoint (failure of the curative treatment approach).
• Health-related quality of life
  • To assess health-related quality of life, the pharmaceutical manufacturer has submitted analyses of the EORTC QLQ-C30.
  • No statistically significant difference was observed between the treatment arms for any of the endpoints: health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning.
  • Consequently, no advantage or disadvantage for Pola + R-CHP can be identified with regard to health-related quality of life.
• Side effects
  • Adverse events (AEs) were recorded in the POLARIX study from the first dose of the study medication until 90 days after the last dose or until the start of follow-up therapy.
  • No statistically significant difference was observed in the incidence of AEs, serious AEs (SAEs), severe AEs or therapy discontinuations due to AEs.
  • In detail, for the specific AEs ‘febrile neutropenia’ (PT, severe AE) and ‘diarrhoea’ (PT, severe AEs), a statistically significant difference was observed in each case to the disadvantage of Pola + R-CHP.
  • Overall, the results regarding side effects do not indicate any advantage or disadvantage of Pola + R-CHP compared with R-CHOP.
• Overall assessment
  • For the endpoint of overall survival, the POLARIX study showed no statistically significant differences between the treatment arms.
  • For the endpoint ‘failure of curative treatment’, operationalised as event-free survival – end of treatment (EFS-EOT), the event-time analysis revealed a statistically significant difference with a minor effect size in favour of Pola + R-CHP, which was not reflected in the event rate. Given the minor effect size and in light of the existing limitations, this finding is not considered sufficiently robust to establish with reasonable certainty an improvement in therapeutic benefit for Pola + R-CHP in this regard.
  • With regard to disease symptoms, assessed using the EORTC QLQ-C30, a statistically significant disadvantage was observed for Pola + R-CHP in the endpoint of pain, the clinical relevance of which is unclear. As regards the other findings on disease symptoms and general health status, the results from the EORTC QLQ-C30, FACT-LymS, FACT/GOG-NtxS and EQ-5D VAS showed no statistically significant differences between the study arms. No statistically significant difference was observed for the B-symptoms assessed either, meaning that neither an advantage nor a disadvantage for Pola + R-CHP can be identified.
  • With regard to quality of life, the results from the EORTC QLQ-C30 showed no statistically significant differences; consequently, neither an advantage nor a disadvantage for Pola + R-CHP in terms of quality of life can be identified.
  • Overall, the endpoints relating to side effects show no relevant differences between Pola + R-CHP and R-CHOP; consequently, neither an advantage nor a disadvantage for Pola + R-CHP can be identified.
  • Overall, there are no differences relevant to the benefit assessment of polatuzumab vedotin. The additional benefit of Pola + R-CHP over R-CHOP for the treatment of adults with previously untreated DLBCL is therefore not proven.

Courtesy translation only, please refer to the German original.