Venetoclax (1) – Venclyxto®

• Clinical trials
  • The pivotal study M13-982 is a single-arm and therefore uncontrolled, open-label Phase II study in which the efficacy and safety of venetoclax were analysed over a median period of approximately two years.
  • In the M14-032 study, which was also a single-arm and consequently non-randomised, open-label Phase II trial, US patients were enrolled following prior treatment with a B-cell receptor inhibitor (BCRi, either ibrutinib (43 patients) or idelalisib (21 patients)), regardless of the presence of a 17p deletion and/or TP53 mutation.

a) Adult patients with CLL who have a 17p deletion or TP53 mutation and who are unsuitable for treatment with a B-cell receptor signalling pathway inhibitor or who have experienced treatment failure

• Adult patients with CLL who have a 17p deletion or TP53 mutation and who are not suitable for treatment with a B-cell receptor signalling pathway inhibitor or who have failed such therapy
• Non-quantifiable additional benefit.
• The G-BA classifies the extent of the non-quantifiable additional benefit of venetoclax on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• An additional benefit exists in accordance with Section 35a(1), sentence 10, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • overall survival
  • In both studies relevant to the assessment, the median overall survival had not yet been reached. In study M13-982, 71.6% of high-risk patients were still alive after 24 months’ follow-up; in study M14-032, 90.2% of patients with recurrent or refractory disease were still alive after 12 months.
• morbidity
  • Progression-free survival
  • The median progression-free survival in study M13-982 was 27.2 months. After 12 months, the endpoint had been reached for 76.7% of the patients enrolled. In study M14-032, 71.7% of patients showed no disease progression and had not died after 12 months. In this study, the median PFS has not yet been reached due to the shorter median follow-up period.
  • The PFS endpoint was defined as the time from study enrolment to disease progression (evidence of progression according to the IWCLL NCI-WG criteria) or death, regardless of the cause of death, whichever occurred first.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Quality of life – EORTC-QLQ-C30 (functional scales)
  • For the ‘global health status’ and ‘role functioning’ scales, study M13-982 found an average improvement of over 10 points from baseline at the 60- and 72-week assessment time points. For the ‘social functioning’ scale, such an improvement was measured at weeks 24, 36, 48, 60, 72 and 84.
  • For all other functional scales, no average change from baseline of at least 10 points was observed at any assessment time point in either study.
  • In the case of follow-up data on patient-reported endpoints, open-label, non-randomised, single-arm studies are generally considered to have a high potential for bias. This high potential for bias is further increased in the present assessment for all patient-reported endpoints (EQ-5D VAS, MDASI and EORTC-QLQ-C30) is further exacerbated by the fact that the investigators in studies M13-982 and M14-032 were able to discontinue a patient’s participation—and thus also the collection of patient-reported endpoints—if that patient did not respond adequately to treatment, for example due to disease progression. Consequently, it cannot be ruled out that informative censoring took place and that, by tendency, healthier patients with a better prognosis were followed up.
• Side effects
  • Adverse events occurred at least once in almost all trial participants receiving venetoclax. Adverse events with a severity grade of CTCAE ≥ 3 occurred in 75.3% of patients in study M13-982 and in 82.8% of patients in study M14-032.
  • Serious adverse events were recorded in 57.6% of patients (M13-982) and 53.1% of patients (M14-032). 23.4% of patients in study M13-982 had to discontinue the study medication due to an adverse event; in 12.0% of patients, an adverse event led to death.
  • Tumour lysis syndrome (TLS)
  • Neutropenia
  • Neutropenia occurred in 45.6% of patients in study M13-982; in study M14-032, it occurred in 59.4% of patients.
  • Infections
  • Infections, including opportunistic infections, occurred in the majority of patients studied in both trials. At least one infection was identified in 76.6% of patients in trial M13-982 and 60.9% of patients in trial M14-032.
  • Secondary malignancies
  • Secondary malignancies occurred during the observation period in 41 patients in study M13-982 (25.9 per cent) and 12 patients in study M14-032 (18.8 per cent).
• Conclusion
  • To assess the extent of the additional benefit of venetoclax, both for the treatment of patients with CLL who have a 17p deletion or TP53 mutation and who are unsuitable for treatment with a B-cell inhibitorsignalling pathway, or who have shown treatment failure, as well as for the treatment of patients with CLL without a 17p deletion or TP53 mutation, in whom treatment failure occurred both during chemo-immunotherapy and during treatment with an inhibitor of the B-cellsignalling pathway, results on mortality, morbidity, quality of life and side effects are available from the registration trials M13-982 and M14-032.
  • However, the limitations described regarding the interpretative value of the available study results—in particular the non-comparative study design—give rise to major uncertainties in the interpretation of the results. Furthermore, results are available only for a minor number of patients from each of the various patient populations comprised within the overall population as defined by the marketing authorisation.
  • The key factors contributing to the inability to quantify the additional benefit in the present case scenario and indication are, the lack of a control group in both studies—even taking into account the unfavourable prognosis of the study population, the majority of whom had a high-risk cytogenetic profile, and the advanced stage of treatment in the patients studied— the uncertainties regarding the external validity of the study population for the target population as defined by the authorised therapeutic indication, and the informative censoring during follow-up for the patient-reported endpoints.

b) Adult patients with CLL without a 17p deletion or TP53 mutation, in whom treatment failure occurred both under chemo-immunotherapy and under a B-cell receptor signalling pathway inhibitor

• Adult patients with CLL without a 17p deletion or TP53 mutation, who have experienced treatment failure both whilst on chemo-immunotherapy and whilst on a B-cell receptor signalling pathway inhibitor
• Non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of venetoclax as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• An additional benefit exists in accordance with Section 35a(1), sentence 10, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• As study M14-032 also included patients with a 17p deletion or TP53 mutation, and who are therefore to be assigned to sub-indication a), the assignment of the respective overall study population to sub-indication a) or b) is not appropriate. Based on the available documentation, it is not possible to assign individual study patients to the two sub-indications with sufficient reliability for all relevant endpoints; for this reason, a separate presentation and evaluation of the results has been omitted.
• mortality
  • overall survival
  • In both studies relevant to the assessment, the median overall survival has not yet been reached. In study M13-982, 71.6% of high-risk patients were still alive after 24 months’ follow-up; in study M14-032, 90.2% of patients with recurrent or refractory disease were still alive after 12 months.
• morbidity
  • Progression-free survival
  • The median progression-free survival in study M13-982 was 27.2 months. After 12 months, the endpoint had been reached for 76.7% of the patients enrolled. In study M14-032, 71.7% of patients showed no disease progression and had not died after 12 months. In this study, the median PFS has not yet been reached due to the shorter median follow-up period.
  • The PFS endpoint was defined as the time from study enrolment to disease progression (evidence of progression according to the IWCLL NCI-WG criteria) or death, regardless of the cause of death, whichever occurred first.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Quality of life – EORTC-QLQ-C30 (functional scales)
  • In study M14-032, an average improvement of over 10 points was measured for the ‘global health status’ scale at week 36 compared with the baseline assessment. For the ‘role functioning’ scale, such an improvement was observed at week 36 and week 48. For the ‘social functioning’ scale, an improvement of at least 10 points was recorded at weeks 36 and 60.
  • For all other functional scales, no average change of at least 10 points from the baseline value was observed at any assessment time point in either study.
  • In the case of follow-up data on patient-reported endpoints, open-label, non-randomised, single-arm studies are generally considered to have a high potential for bias. This high potential for bias is further exacerbated in the present assessment for all patient-reported endpoints (EQ-5D VAS, MDASI and EORTC-QLQ-C30) is further exacerbated in this assessment by the fact that the investigators in studies M13-982 and M14-032 were able to terminate a patient’s participation – and thus also the collection of patient-reported endpoints – if that patient did not respond adequately to treatment, for example due to disease progression.
• Side effects
  • Adverse events occurred at least once in almost all study participants receiving venetoclax. Adverse events with a severity grade of CTCAE ≥ 3 occurred in 75.3% of patients in study M13-982 and in 82.8% of patients in study M14-032.
  • Tumour lysis syndrome (TLS)
  • Neutropenia
  • Infections
  • Secondary malignancies
• Conclusion
  • To assess the extent of the additional benefit of venetoclax, both for the treatment of patients with CLL who have a 17p deletion or TP53 mutation and who are unsuitable for treatment with a B-cell inhibitorsignalling pathway, or who have experienced treatment failure, as well as for the treatment of patients with CLL without a 17p deletion or TP53 mutation, in whom treatment failure occurred both during chemo-immunotherapy and during treatment with a B-cellsignalling pathway, results on mortality, morbidity, quality of life and side effects are available from the registration trials M13-982 and M14-032.
  • However, the limitations described regarding the interpretative value of the available study results—in particular the non-comparative study design—give rise to major uncertainties in the interpretation of the results. Furthermore, results are available only for a minor number of patients from each of the various patient populations included in the overall population as defined by the marketing authorisation. For the sub-indication of patients without a 17p deletion and/or TP53 mutation, the number is fewer than 32 patients.
  • The key factors contributing to the inability to quantify the additional benefit in this specific case scenario and indication are, the lack of a control group in both studies – even taking into account the unfavourable prognosis of the study population, the majority of whom had a high-risk cytogenetic profile, and the advanced stage of treatment in the patients studied – the uncertainties regarding the external validity of the study population for the target population as defined by the authorised therapeutic indication, and the informative censoring observed during follow-up for the patient-reported endpoints.

Courtesy translation only, please refer to the German original.