Polatuzumab Vedotin (2) – 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)

• In summary, the additional benefit of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP) is assessed as follows:
• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification
• mortality
  • The endpoint of overall survival was defined in the POLARIX trial as the time from randomisation to death from any cause.
  • With regard to the overall survival endpoint, 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 – Event-Free Survival (EFS)
  • The endpoint ‘event-free survival’ (EFS) was defined in the POLARIX study as the time between randomisation and the first occurrence of any of the following events: disease progression or recurrence; initiation of a new anti-lymphoma therapy (an efficacy event, as assessed by the clinical trial staff, other than progression or recurrence, leading to the initiation of a new anti-lymphoma therapy not specified in the protocol (Next Anti-Lymphoma Therapy, NALT), e.g. confirmed residual disease or suspected residual disease), a biopsy after the end of treatment confirming residual disease, regardless of whether NALT was initiated or not, or death from any cause.
  • The results for the EFS endpoint show a statistically significant difference in favour of Pola + R-CHP.
  • The statistically significant difference is based on a hazard ratio (HR) of 0.785, an upper 95% confidence interval limit of 0.999 and a p-value of 0.0484, indicating a difference that is only just statistically significant.
  • Overall, this marginally statistically significant difference in EFS is not considered sufficiently robust, given the minor effect size 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 potential cure through the present curative therapeutic approach.
• quality of life
  • Based on the results of the MMRM analyses of the EORTC QLQ-C30 scales and the FACT-LymS, as well as the time to deterioration of ≥ 10 points on the physical functioning scale of the EORTC QLQ-C30, no statistically significant difference was observed between the treatment groups.
  • Consequently, neither an advantage nor a disadvantage for Pola + R-CHP can be identified with regard to 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) or severe AEs, or in therapy discontinuations due to AEs.
  • In detail, a statistically significant disadvantage of Pola + R-CHP was observed for AEs in the system organ class (SOC) ‘infections and parasitic diseases’.
  • In addition, febrile neutropenia and diarrhoea occurred more frequently with Pola + R-CHP.
  • A disadvantage for Pola + R-CHP was also observed with regard to severe febrile neutropenia.
  • By contrast, a statistically significant advantage for Pola + R-CHP was observed for the SOC ‘cardiac disorders’.
  • No statistically significant difference was observed with regard to SAE or AEs of particular interest.
  • Overall, the results on 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.
  • In the morbidity endpoint category, a marginally statistically significant difference was observed in the event-free survival (EFS) endpoint in favour of Pola + R-CHP, which, due to the minor size of the effect and the existing limitations, is not considered sufficiently robust to establish with reasonable certainty an improvement in therapeutic benefit for Pola + R-CHP in this regard.
  • The results for the disease-free survival endpoint (DFS) are not used to quantify the extent of the additional benefit due to the overall uncertainties arising from the breach of randomisation and the operationalisation of DFS used in this study, and in view of the only marginally statistically significant effect.
  • With regard to the patient-reported endpoints of disease symptoms and general health status, no statistically significant differences were observed between the study arms; consequently, neither an advantage nor a disadvantage for Pola + R-CHP can be identified.
  • The clinical relevance of the statistically significant effect observed for the endpoint ‘chemotherapy-induced neurotoxicity’ is unclear.
  • With regard to quality of life, the results from the EORTC QLQ-C30 and FACT-LymS showed no statistically significant differences; consequently, neither an advantage nor a disadvantage for Pola + R-CHP in terms of quality of life can be established.
  • Overall, the endpoints relating to side effects show no relevant difference between Pola + R-CHP and R-CHOP; consequently, neither an advantage nor a disadvantage for Pola + R-CHP can be established.
  • Overall, the G-BA classifies the extent of the additional benefit of Pola + R-CHP as non-quantifiable, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.