Polatuzumab Vedotin (1) – Polivy®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the pivotal, multicentre, multi-arm, open-label Phase Ib/II trial GO29365 for the benefit assessment.

Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for haematopoietic stem cell transplantation

• mortality
  • Overall survival is defined in the GO29365 trial as the time from randomisation to death from any cause.
  • As of the data cut-off date of 2 January 2020, 26 patients in the intervention arm (65.0%) and 29 in the control arm (72.5%) had died. The median survival time was 12.4 months in the intervention arm compared with 4.7 months in the control arm, with a median follow-up of approximately 42 months for the study arms. This corresponds to a median survival benefit of 7.7 months.
  • In the time-to-event analysis, stratified by the duration of response to the last treatment (≤ 12 vs. > 12 months), a statistically significant difference was observed (hazard ratio (HR): 0.42; 95% confidence interval (CI): [0.24; 0.73]; p-value = 0.0014) in favour of polatuzumab vedotin in combination with bendamustine and rituximab.
  • A significant advantage of treatment with polatuzumab vedotin in combination with bendamustine and rituximab was observed in terms of overall survival.
• Morbidity – Complete Response (CR)
  • In the GO 29365 trial, the endpoint ‘complete response’ (CR) was defined as the proportion of patients achieving a complete response at the time of the primary response assessment (6–8 weeks after Day 1 of Cycle 6 or the last administration of the study medication).
  • A complete response (CR) was observed in 16 patients (40%) in the intervention arm and 7 patients (17.5%) in the control arm. The difference is statistically significant in favour of polatuzumab vedotin in combination with bendamustine and rituximab.
  • The endpoint of complete response (CR) is an important prognostic factor and is relevant to treatment decisions. A CR associated with a reduction in disease symptoms that is noticeable to the patient is fundamentally relevant to the benefit assessment. In the GO29365 study, the CR endpoint was assessed using imaging procedures based on the modified Lugano criteria. The endpoints were therefore not assessed on the basis of symptoms, but on the basis of asymptomatic findings. No valid data on disease-related symptoms are available from the GO29365 study.
  • There is no validation of CR as a surrogate parameter for patient-relevant endpoints, e.g. mortality. Therefore, in this assessment, CR is classified as an endpoint of unclear relevance and is presented only as supplementary information. No conclusions can be drawn regarding the extent of the additional benefit.
• quality of life
  • No data on health-related quality of life were collected in the GO29365 study. No conclusions can be drawn from the GO29365 study regarding the extent of the additional benefit in terms of quality of life.
• Side effects – Total adverse events (AEs)
  • Almost all patients in the intervention and control arms experienced an adverse event. The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
• Overall assessment
  • For the benefit assessment of polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for haematopoietic stem cell transplantation, results from the GO29365 study on overall survival, morbidity and side effects are available, compared with the combination of bendamustine and rituximab. For the evaluation of this multi-arm study, the randomised controlled comparison of study arms C (intervention arm) and D (control arm) is used.
  • In the mortality endpoint category, a statistically significant advantage was observed in favour of polatuzumab vedotin in combination with bendamustine and rituximab. A significant advantage was observed compared with treatment with bendamustine in combination with rituximab.
  • No conclusions can be drawn from the available results on the morbidity endpoint ‘complete response’ regarding the extent of the additional benefit. With regard to symptoms, the results from the neuropathy-specific questionnaire TINAS cannot be used due to its lack of validity.
  • No data on health-related quality of life were collected in the study; therefore, no conclusion can be drawn regarding the extent of the additional benefit in terms of quality of life.
  • Overall, the results on side effects show no differences relevant to the assessment.
  • The overall assessment of the extent of the additional benefit takes into account that the results from study GO29365 are subject to significant uncertainties and limitations. One source of minor uncertainty in study GO29365 is its minor sample size, with only 40 patients each in the intervention and control arms. Consequently, all available effect estimates for patient-relevant endpoints are based on comparatively small numbers of cases. In particular, the effect estimate for overall survival is based on only 26 events in the intervention arm and 29 events in the control arm.
  • Furthermore, there are imbalances regarding the baseline characteristics of the patients included in the study arms. In particular, the proportion of patients with an IPI (International Prognostic Index) score of 4–5 was 22.5% in the intervention arm and 42.5% in the control arm. Bulky disease was present in 25% of patients in the intervention arm and 37.5% of patients in the control arm. Both of these characteristics are of prognostic relevance, at least in early lines of treatment. These random imbalances could therefore lead to a bias in favour of polatuzumab vedotin in combination with bendamustine and rituximab.
  • A further significant limitation of the GO29365 study is that the BR regimen used in the control arm does not correspond to the currently preferred treatment options for non-transplantable patients in second-line treatment of r/r DLBCL within the German healthcare context.
  • Finally, a limiting factor is that, based on the GO29365 study, no conclusions can be drawn regarding the extent of the additional benefit in terms of morbidity and quality of life.
  • The extent of the limitations and uncertainties described in the present study results is assessed, on balance, as so significant that, despite the substantial advantage in overall survival, it does not permit an overall quantification of the additional benefit.

Courtesy translation only, please refer to the German original.