Ponatinib (1) – Iclusig®

• Clinical trials
  • To answer the question regarding the extent of the additional benefit, the results of the registration trial AP24534-10-201 and the Phase I dose-finding trial AP24534-07-101, which supported the marketing authorisation, are available.
  • The assessment of the extent of the additional benefit of ponatinib is based on the AP24534-10-201 trial. This trial is a multicentre, single-arm, open-label Phase II trial.

a) Adult patients with chronic myeloid leukaemia (CML)

• In summary, the extent of the additional benefit of ponatinib is assessed as follows: For adult patients with chronic myeloid leukaemia in the chronic phase, accelerated phase or blast crisis who are resistant to treatment with dasatinib or nilotinib, who are unable to tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who harbour a T315I mutation, there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the non-quantifiable additional benefit of ponatinib 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 treating the disease. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• Factors relevant to the decision in the present case and indication are the short follow-up period of 9.9 months, the absence of a control group in the study, and the methodologically inadequate historical control presented in the dossier.
• Consequently, it is not possible, on the basis of the data provided, to make a quantitative assessment of the extent of the effect or to quantify the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’.
• mortality
  • By the data cut-off date of 27 April 2012, median overall survival had not been reached in the CP-CML and AP-CML groups. In the BK-CML group, median overall survival was 29.9 weeks.
  • The 12-month survival rate was 93.5% for CP-CML (R/I cohort: 94.4%; T315I cohort: 90.2%), for AP-CML 82.2% (R/I cohort: 83.9%; T315I cohort: 72.2%) and for BK-CML 29.5% (R/I cohort: 35.1%; T315I cohort: 16.0%).
  • There is no control group. Furthermore, the historical control is methodologically inadequate. The scientific data therefore do not allow for a quantification of the extent of the additional benefit of ponatinib in terms of mortality.
• Morbidity – Haematological Response (HR)
  • The rate of major haematological response (MaHR) is the primary endpoint for patients in the advanced stages of CML (AP-CML and BK-CML) and is defined as the proportion of patients who achieved a complete haematological response (Complete Haematologic Response, CHR) or No Evidence of Leukaemia (NEL) after the start of the study and who, upon reassessment of the response rate 28 days after the first assessment, continued to meet the CHR or NEL criteria.
  • A total of 48 out of 83 patients in the AP-CML cohort (57.8%) achieved a MaHR. When the R/I and T315I cohorts were analysed separately, the figures were 39 out of 65 patients (60.0 %) and 9 out of 18 patients (50 %), respectively.
  • In the BK-CML cohort, a total of 19 out of 62 patients (30.6%) achieved a MaHR. When the R/I and T315I cohorts were considered separately, the figures were 12 out of 38 patients (31.6 per cent) and 7 out of 24 patients (29.2 per cent), respectively.
  • Particularly due to the methodologically inadequate historical control, but also the lack of a control group, it is not possible to draw conclusions regarding the extent of the additional benefit.
• Morbidity – Cytogenetic Response (CyR)
  • For patients in the chronic phase of CML, the primary endpoint of the study is major cytogenetic response (MCyR). MCyR is defined as the proportion of patients who received at least one dose of the study medication and who achieved a complete cytogenetic response (Complete Cytogenetic Response, CCyR) or a partial cytogenetic response (Partial Cytogenetic Response, PCyR) after the start of the study.
  • 144 of the 267 patients (53.9%) in the CP-CML cohort achieved an MCyR whilst on ponatinib, including 118 (44.2%) who achieved a CCyR. When the R/I and T315I cohorts were analysed separately, 99 out of 203 patients (48.8 %) in the R/I cohort achieved an MCyR, including 76 (37.4 %) patients who achieved a CCyR; in the T315I cohort, 45 out of 64 patients (70.3%) achieved an MCyR, including 42 (65.6%) who achieved a CCyR.
  • Particularly due to the methodologically inadequate historical control, but also the lack of a control group, it is not possible to draw conclusions regarding the extent of the additional benefit.
• Morbidity – Molecular Response (MR)
  • The dossier reports a good molecular response (Major Molecular Response, MMR) is reported, defined as the proportion of patients who met the criteria for an MMR (ratio of ≤ 0.1 % of BCR-ABL to ABL transcripts on the International Scale) at least once after the start of the study.
  • A total of 79 out of 267 patients (29.6 %) in the CP-CML cohort achieved an MMR. When the R/I and T315I cohorts were analysed separately, 47 out of 203 patients (23.2 %) in the R/I cohort achieved an MMR; in the T315I cohort, 32 out of 64 patients (50 %) achieved MMR.
  • Particularly due to the lack of a control group, it is not possible to draw conclusions regarding the extent of the additional benefit.
• quality of life
  • Quality of life was not assessed in the AP24534-10-201 study. Consequently, no data are available to evaluate the additional benefit of ponatinib in terms of quality of life.
• Side effects
  • Overall, 99.3% of the 417 CML patients experienced at least one adverse event.
  • In CP-CML, 99.3% of patients experienced at least one AE. The most common adverse events in the CP-CML group were thrombocytopenia (42.2%), rash (40.7%) and abdominal pain (38.1%).
  • In the AP-CML group, 98.8% of patients experienced at least one AE. The most common AEs were thrombocytopenia (47.1%), neutropenia (31.8%) and abdominal pain (30.6%).
  • In BK-CML, all patients experienced at least one AE, the most common of which were rash (33.9%), thrombocytopenia (33.9%) and neutropenia (33.9%).
  • Among 417 patients with CML, 204 (48.9%) experienced at least one serious adverse event (SAE).
  • The most common AEs of grade ≥ 3 in the CP-CML population were thrombocytopenia (33%), neutropenia (15.7%) and elevated lipase levels (11.2%).
  • A total of 49 CML patients (11.8%) discontinued treatment with ponatinib due to adverse events.
  • However, valid conclusions regarding the extent of the additional benefit in terms of adverse events cannot be drawn from the available data due to the lack of long-term data and the limitation of the absence of a control group.

Adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) with the T315I mutation

• In summary, the extent of the additional benefit of ponatinib is assessed as follows: For adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have a T315I mutation, there is a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of ponatinib 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 treating the disease. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• Factors relevant to the decision in the present case and indication are the short follow-up period of 9.9 months, the minor number of cases, the absence of a control group in the study, and the methodologically inadequate historical control presented in the dossier.
• Consequently, it is not possible, on the basis of the data provided, to make a quantitative assessment of the extent of the effect or to quantify the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’.
• mortality
  • Up to the data cut-off date of 27 April 2012, the median overall survival was 39.3 weeks in the Ph+ ALL population.
  • The 12-month survival rate was 42.3% (50.0% in the R/I cohort; 39.0% in the T315I cohort).
  • No control group is available. Furthermore, the historical control is methodologically inadequate. The scientific data therefore do not permit a quantification of the extent of the additional benefit of ponatinib in terms of mortality.
• Morbidity – Haematological Response (HR)
  • The primary endpoint for patients with Ph+ ALL is MaHR. A total of 13 out of 32 patients (40.6%) achieved MaHR. When the R/I and T315I cohorts were considered separately, these figures were 5 out of 10 patients (50.0 %) and 8 out of 22 patients (36.4 %), respectively.
  • Particularly due to the methodologically inadequate historical control, the minor sample sizes and the lack of a control group, no conclusions can be drawn regarding the extent of the additional benefit.
• Morbidity – Cytogenetic Response (CyR)
  • Data on the MCyR endpoint are available for patients with Ph+ ALL. 15 of the 32 Ph+ ALL patients (46.9%) achieved an MCyR (6 patients in the R/I cohort and 9 patients in the T315I cohort), including 12 (37.5%) who achieved a CCyR.
  • Particularly due to the methodologically inadequate historical control, the minor sample sizes, and also the lack of a control group, it is not possible to draw conclusions regarding the extent of the additional benefit.
• Morbidity – Molecular Response (MR)
  • A total of 3 out of 32 Ph+ ALL patients (9.4%) achieved an MMR. This corresponds to 2 patients (20%) in the R/I cohort and 1 patient (4.5%) in the T315I cohort.
  • Particularly due to the minor number of cases, but also because of the lack of a control group, no conclusions can be drawn regarding the extent of the additional benefit.
• Morbidity – Progression-free survival (PFS)
  • For the Ph+ ALL indication, the definition of progression was the same as that for BK-CML.
  • Owing to the limitations already mentioned, no conclusions regarding the quantification of patient-relevant additional benefit can be drawn on the basis of the PFS endpoint.
• quality of life
  • Quality of life was not assessed in the AP24534-10-201 study. Consequently, no data are available to evaluate the additional benefit of ponatinib in terms of quality of life.
• Side effects
  • In the Ph+ ALL population, all patients experienced at least one adverse event. The most common events were constipation (46.9%), abdominal pain (31.3%) and fatigue (25%).
  • Twenty-three patients (71.9%) experienced at least one serious adverse event. The most common events were febrile neutropenia (21.9%), neoplastic progression (12.5%) and sepsis (9.4%).
  • The most common AEs of grade ≥ 3 were febrile neutropenia (25%), neutropenia (21.9%) and anaemia (18.8%).
  • In total, one ALL patient (3.1%) discontinued treatment with ponatinib due to adverse events.
  • However, valid conclusions regarding the extent of the additional benefit in terms of adverse events cannot be drawn from the available data, due to the lack of long-term data and the limitation of the absence of a control group.
• Overall assessment
  • In its overall assessment of the available results, the G-BA, based on the marketing authorisation and the desired and adverse effects observed in the aforementioned study, and taking into account the comments received, the oral hearing and the severity of the condition, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit this.

Courtesy translation only, please refer to the German original.