Ibrutinib (1) – Imbruvica®

• Clinical trials
  • The PCYC-1104-CA trial is a single-arm, open-label study involving 111 adult patients with relapsed or refractory mantle cell lymphoma, designed to investigate the efficacy and safety of ibrutinib.
  • The PCYC-1112-CA study is a randomised, actively controlled, open-label, multicentre Phase III study designed to investigate the efficacy and safety of ibrutinib compared with ofatumumab.
  • The marketing authorisation for ibrutinib for the indication of CLL is also based on the results of the single-arm Phase Ib/II study PCYC-1102-CA.

Treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL)

• For adult patients with relapsed or refractory mantle cell lymphoma, ibrutinib offers a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of ibrutinib for the indication of MCL 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.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • The secondary endpoint of overall survival was defined as the time from the first administration of the study medication until death from any cause.
  • The median overall survival in the PCYC-1104-CA study was 22.5 months [95% CI: 13.7 months; not reached].
  • Even when taking into account median survival times previously observed in comparable patient cohorts, a qualitative advantage of ibrutinib appears plausible. However, as PCYC-1104-CA is a single-arm study, the additional benefit of ibrutinib for the mortality endpoint category cannot be quantified.
• Morbidity – Progression-free survival
  • The secondary endpoint PFS was defined as the time from the start of treatment to disease progression or death from any cause, whichever occurred first.
  • The median progression-free survival in the PCYC-1104-CA study was 13.0 months [95% CI: 7.0 months; 17.5 months].
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the secondary endpoint of overall survival. Furthermore, the ‘disease progression’ component of morbidity in PFS was not primarily assessed on the basis of symptoms, but rather using imaging and laboratory procedures. Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the relevance of the PFS endpoint to patients. This does not affect the overall assessment of the extent of the additional benefit.
• Morbidity – Overall Response Rate
  • The primary endpoint, overall response rate, was defined as the proportion of patients who demonstrated a complete or partial response (including a defined reduction in the size of the lymph nodes, the volume of the liver or spleen, no evidence of bone marrow infiltration) in accordance with the IWG Revised Response Criteria for Malignant Lymphoma in response to the study medication.
  • Theoverall response rate(ORR, according to IRC assessment) was 68.5% (95% CI: 59.0%; 77.0%) at the data cut-off date of 3 March 2014.
  • The assessment of the overall response rate endpoint was therefore not primarily based on symptoms, but mainly on imaging and laboratory procedures; consequently, this endpoint alone is not considered directly patient-relevant. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (EORTC-QLQ-C30)
  • The response rate for the EORTC-QLQ-C30 at cycle 10 was only 49 per cent, at cycle 16 just 29 per cent, and at cycle 22 only around 6 per cent. Due to the unblinded nature of the data collection in this single-arm trial and the minor response rate, the results for this endpoint must be regarded as potentially highly biased. Owing to the resulting insufficient statistical power, the results have not been presented. It is not possible to quantify the extent of the additional benefit of ibrutinib from these data.
  • Furthermore, there is no clinically relevant change in the mean differences between cycle 10 and baseline, nor between cycle 16 and baseline.
• Quality of life – EORTC-QLQ-C30 (quality of life)
  • The response rate for the EORTC-QLQ-C30 at cycle 10 was only 49%, at cycle 16 just 29%, and at cycle 22 only around 6%. Due to the unblinded data collection in the single-arm trial and the low response rate, the results for this endpoint must be regarded as potentially highly biased. Owing to the resulting insufficient statistical power, the results have not been presented. It is not possible to quantify the extent of the additional benefit of ibrutinib from these data.
  • Furthermore, there is no clinically relevant change – defined as a difference of at least 10 points – in the mean differences between cycle 10 and baseline, nor between cycle 16 and baseline.
• Side effects
  • All patients in the PCYC-1104-CA study experienced at least one adverse event during treatment with ibrutinib, with diarrhoea, fatigue and nausea being the most common.
  • An adverse event of CTCAE grade ≥ 3 occurred in 81.1% of patients, and a serious adverse event in 63.1% of patients.
  • The most common serious adverse events were pneumonia, atrial fibrillation and urinary tract infections.
  • 13.5% of patients had to interrupt treatment due to an adverse event, and in 16.2% of patients, an adverse event led to death.
• Conclusion
  • Quantitative conclusions regarding the extent of the additional benefit of ibrutinib in the indication for MCL cannot be drawn from the results of the single-arm PCYC-1104-CA study.
  • Due to the methodological limitations of the study, and taking into account previously described descriptive study results on overall survival in similar patient cohorts, the G-BA concludes that ibrutinib offers a non-quantifiable additional benefit for the indication of MCL.

a) Treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior course of therapy

• mortality
  • The secondary endpoint of overall survival was defined as the time from randomisation to death from any cause.
  • Median overall survival was not reached in the PCYC-1112-CA study in either the intervention or control arm. However, a statistically significant difference was observed between the two arms with regard to the Kaplan-Meier curves (HR 0.434 [95% CI: 0.238; 0.789], p = 0.0049).
  • A subgroup analysis showed that this difference was observed only in patients who were refractory to prior treatment with a purine analogue (HR 0.26 [95% CI: 0.10; 0.65], p = 0.004). Furthermore, only patients with poorer health status (ECOG ≥ 1) derive a statistically significant greater benefit from treatment with ibrutinib (HR 0.26 [95% CI: 0.12; 0.54], p = 0.0003).
  • The data on overall survival are to be regarded as immature due to the relatively short duration of the study compared with the remaining life expectancy and the minor number of events.
  • Due to the crossover of a significant number of patients from the control arm, it must be assumed that the results are biased, which could lead to an underestimation of the treatment effect of ibrutinib.
  • Based on these considerations, the G-BA concludes that there is a non-quantifiable additional benefit for ibrutinib with regard to the endpoint of mortality.
• Morbidity – Progression-free survival
  • The primary endpoint of the PCYC-1112-CA study, progression-free survival, was defined as the time from randomisation to disease progression or death from any cause, whichever occurred first.
  • In the PCYC-1112-CA study, the median progression-free survival was 8.1 months in the ofatumumab arm and had not yet been reached in the ibrutinib arm. The Kaplan-Meier curve for PFS showed a statistically significant difference in favour of ibrutinib (HR 0.215 [95% CI: 0.146; 0.317], p ≤ 0.0001).
• Quality of life – EORTC-QLQ-C30 (quality of life)
  • With regard to the scale scores on the functional scales of the EORTC-QLQ-C30, the differences in mean scores do not indicate a statistically significant difference between the treatment arms.
  • Due to the unblinded nature of the open-label study, the results for this endpoint should be regarded as potentially highly biased. Furthermore, there are major differences in the response rates between the two treatment arms (67% vs. 55% at week 24, based on the ITT population). The results are therefore presented for supplementary information only.
  • As fewer than 3% of the patients enrolled at the start of the study were included in the analysis at week 60, these results are not presented due to their lack of statistical significance.
• Side effects
  • Almost all patients in the PCYC-1112-CA study experienced at least one adverse event during treatment with ibrutinib and also with ofatumumab (99.5% vs. 97.9%).
  • Diarrhoea and fever occurred more frequently during treatment with ibrutinib (47.7% vs. 17.8% and 23.6% vs. 14.7%, respectively). Infusion-related reactions occurred more frequently with ofatumumab (0% vs. 27.7%).
  • In 56.9% of patients treated with ibrutinib, an adverse event of CTCAE grade ≥ 3 occurred, and 41.5% of patients experienced a serious adverse event. In the ofatumumab arm, 47.1% of patients experienced an adverse event of CTCAE grade ≥ 3, and 30.4% of patients experienced a serious adverse event.
  • The most common serious adverse event was pneumonia.
  • 8.2% vs. 8.4% of patients had to interrupt treatment due to an adverse event, and in 6.2% vs. 8.4% of patients, an adverse event led to death.
  • When considering the crude incidence rates, significantly more serious adverse events occurred with ibrutinib (RR: 1.37 [95% CI: 1.04; 1.8]; p = 0.012) and adverse events with a severity grade of CTCAE ≥ 3 (RR: 1.21 [95% CI: 1.00–1.47]; p = 0.028) were observed. However, when considering the exposure-adjusted incidence rates, the differences are no longer statistically significant.
  • In the overall assessment of the results on side effects, therefore, proof that ibrutinib causes greater harm is not proven, and the overall conclusion regarding the extent of the additional benefit remains unaffected.
• Conclusion
  • The data on overall survival for previously treated patients with CLL must, however, be regarded as immature.
  • A median overall survival was not reached in either study arm due to the small number of deaths; the significant advantage in overall survival is derived from the hazard ratio of the Kaplan-Meier curves.
  • The differences between the intervention and control arms for the patient-relevant endpoints PFS and overall response rate – which are not directly relevant to patients – are, however, pronounced in a way which has scarcely been observed to date in comparable patient cohorts for this indication in clinical trials, and thus support the finding regarding the additional benefit for the endpoint of overall survival.
  • Subgroup analyses also show, however, that patients with varying health statuses and differing responses to prior treatment benefit to varying degrees from treatment with ibrutinib. It is not possible to quantify the additional benefit for the overall population under consideration in this scenario.
  • Furthermore, given the inclusion criteria, it cannot be ruled out that a more intensive treatment option might have been considered for some patients in the comparator arm receiving ofatumumab, which could have led to the overall survival results in both study arms becoming more similar.
  • Although the positive overall survival results are not offset by a significant increase in side effects, the results are also not supported by advantages in terms of symptoms or quality of life.
  • Taking all the results into account, the G-BA recognises an additional benefit of ibrutinib. However, as the results are heterogeneous and mature mortality data are not available, it is not possible to quantify the additional benefit for pre-treated patients with CLL.

b) First-line therapy for patients with a 17p deletion or a TP53 mutation who are not suitable for chemo-immunotherapy

• For adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior course of treatment, or patients receiving first-line therapy with a 17p deletion or a TP53 mutation who are not suitable for chemo-immunotherapy, ibrutinib offers a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of ibrutinib for the indication of CLL as non-quantifiable, based on the criteria 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.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• For patients with chronic lymphocytic leukaemia and a 17p deletion or TP53 mutation who are unsuitable for first-line treatment with chemoimmunotherapy, there are no relevant study data available on treatment with ibrutinib. Only two patients in the single-arm PCYC-1102-CA trial were treatment-naive and also had a relevant mutation.
• The basis for marketing authorisation for this sub-indication is the results of subgroup analyses from the PCYC-1112-CA trial (previously treated patients) regarding the endpoints of overall survival, progression-free survival, overall response and side effects, supported by the results of the PCYC-1102-CA trial.
• As the extrapolation of trial results from previously treated to untreated patients is associated with major uncertainties, the extent of which cannot be determined with sufficient certainty, the G-BA concludes that it is not possible to quantify the extent of the additional benefit of ibrutinib in this sub-indication.

Courtesy translation only, please refer to the German original.