Capivasertib (1) – Truqap®

• Clinical trials
  • The CAPItello-291 trial is an ongoing, multicentre, randomised, controlled (RCT) Phase III trial comparing capivasertib in combination with fulvestrant against placebo in combination with fulvestrant.
  • The ongoing FAKTION trial is a two-part study comprising an initial dose-escalation phase followed by a double-blind, multicentre Phase II trial. For the purposes of the benefit assessment, the randomised part of the trial will be used, in which capivasertib in combination with fulvestrant was compared with placebo in combination with fulvestrant.

a1) Women with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration(s), following recurrence of the disease during or after (neo-)adjuvant endocrine therapy, who have not previously received treatment at the locally advanced or metastatic stage

• An additional benefit is not proven.
• mortality
  • The CAPItello-291 study showed no statistically significant difference in overall survival for patients. The median survival has not yet been reached due to the minor number of events.
• Morbidity – Progression-free survival
  • A statistically significant advantage was observed for PFS in favour of capivasertib in combination with fulvestrant compared with fulvestrant alone.
  • The results for the PFS endpoint are not included in this assessment.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • For the endpoint of diarrhoea, there is a statistically significant difference in favour of capivasertib in combination with fulvestrant compared with fulvestrant alone that is associated with a disadvantage.
  • For the other symptoms – fatigue, pain, nausea and vomiting, dyspnoea, insomnia, loss of appetite and constipation – as assessed using the EORTC QLQ-C30 – as well as the side effects of systemic therapy, symptoms in the chest area and symptoms in the arm area – as assessed using the EORTC QLQ-BR23 – no differences were observed.
  • No suitable data are available for the symptom ‘distress due to hair loss’.
• Morbidity – Symptoms (PGIS)
  • No suitable data are available for the endpoint ‘symptoms’, as assessed using the PGIS.
• Morbidity – Health status (EQ-5D, Visual Analogue Scale)
  • No statistically significant difference was observed between the treatment arms for health status, as assessed using the EQ-5D VAS.
• Morbidity – Health status (PGIC)
  • No suitable data are available for the health status endpoint, as assessed using the PGIC.
• morbidity
  • In the morbidity endpoint category, a disadvantage is identified due to the negative effect on the diarrhoea endpoint.
• Quality of life (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • For the scales measuring global health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning, assessed using the EORTC QLQ-C30, as well as the scales measuring body image, sexual activity and outlook on the future, assessed using the EORTC QLQ-BR23, no statistically significant difference was observed in any case.
  • For the ‘enjoyment of sex’ scale, assessed using the EORTC QLQ-BR23, no suitable data are available, as 81% and 93% of patients, respectively, had no baseline or post-baseline score.
• Side effects – Total adverse events (AEs)
  • In the CAPItello-291 study, AEs occurred in all patients in the capivasertib arm and in 80% of patients in the control arm. The results are presented here for supplementary information only.
• Side effects – Serious SAEs and severe AEs
  • No statistically significant differences were observed between the treatment groups for the endpoints of SAEs and severe AEs.
• Side effects – Discontinuation due to AEs and PRO-CTCAE
  • No information is available as to whether discontinuation due to an AE involved discontinuation of at least one or all active ingredients (INN). As no data on discontinuations are available broken down by active ingredient (INN), the results are not suitable for a benefit assessment.
  • The PRO-CTCAE questionnaire is not used due to the non-transparent selection process and the non-traceable selection of items for mapping the symptomatic AEs of capivasertib and fulvestrant.
• Side effects – Specific AEs (diarrhoea, maculopapular rash, stomatitis, gastrointestinal disorders)
  • For the endpoints diarrhoea, maculopapular rash and stomatitis, as well as for the endpoint gastrointestinal disorders, a statistically significant disadvantage was observed between the treatment groups in favour of capivasertib in combination with fulvestrant.
• Overall assessment
  • In its overall assessment, the G-BA concludes that, for capivasertib in combination with fulvestrant for the treatment of female patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations, following recurrence of the disease during or after (neo-)adjuvant endocrine therapy and who have not previously received treatment at the locally advanced or metastatic stage, additional benefit is not proven compared with placebo in combination with fulvestrant.

a2) Men with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration(s), following recurrence of the disease during or after (neo-)adjuvant endocrine therapy, who have not previously received treatment at the locally advanced or metastatic stage

• An additional benefit is not proven.
• The pharmaceutical manufacturer has not provided any data for the assessment of the additional benefit of capivasertib compared with the appropriate comparator therapy.
• Overall assessment
  • The G-BA therefore concludes that, for capivasertib in combination with fulvestrant in men with PIK3CA/AKT1/PTEN alterations, ER-positive, HER2-negative, locally advanced or metastatic breast cancer and a recurrence of the disease during or after (neo-)adjuvant endocrine therapy, who have not previously received treatment at the locally advanced or metastatic stage, additional benefit over placebo in combination with fulvestrant is not proven.

b1) Women with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration(s), with disease progression during or after endocrine therapy administered at the locally advanced or metastatic stage

• Indication of a considerable additional benefit.
• mortality
  • The meta-analytical evaluation reveals a statistically significant difference between the treatment arms for the endpoint of overall survival, in favour of capivasertib in combination with fulvestrant. The extent of the prolongation in overall survival achieved is considered a significant advantage.
• Morbidity – Progression-free survival
  • A statistically significant advantage was observed for PFS, favouring capivasertib in combination with fulvestrant.
• Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • For the symptom of constipation, there was a statistically significant advantage in favour of capivasertib in combination with fulvestrant.
  • For the symptoms of loss of appetite, diarrhoea, and nausea and vomiting, there was a statistically significant disadvantage compared with capivasertib in combination with fulvestrant compared with fulvestrant alone.
  • For the other symptoms – fatigue, pain, as well as dyspnoea and insomnia – assessed using the EORTC QLQ-C30 – and side effects of systemic therapy, symptoms in the chest area and symptoms in the arm area – assessed using the EORTC QLQ-BR23 – neither advantages nor disadvantages were identified.
  • No suitable data are available for the symptom of distress caused by hair loss.
• Morbidity – Symptoms (PGIS)
  • No suitable data are available for the endpoint ‘symptoms’, as assessed using the PGIS.
• Morbidity – Health status (EQ-5D, Visual Analogue Scale)
  • No statistically significant difference in health status was observed between the treatment arms.
• Morbidity – Health status (PGIC)
  • No suitable data are available for the health status endpoint, as assessed by the PGIC.
• morbidity
  • In the morbidity endpoint category, an overall disadvantage is observed due to the negative effects.
• Quality of life (EORTC QLQ-C30 and EORTC QLQ-BR23)
  • For the social functioning endpoint, a statistically significant difference was observed between the treatment groups, with a disadvantage for capivasertib in combination with fulvestrant.
  • For the scales measuring global health status, physical functioning, role functioning, emotional functioning and cognitive functioning, assessed using the EORTC QLQ-C30, as well as the scales for body image, sexual activity and future prospects, assessed using the EORTC QLQ-BR23, no statistically significant difference was observed in any case.
  • For the ‘enjoyment of sex’ scale, assessed using the EORTC QLQ-BR23, no suitable data are available, as 83% and 81% of patients, respectively, had no baseline or post-baseline score.
• Side effects – Total adverse events (AEs)
  • In the CAPItello-291 study, AEs occurred in almost all patients in the capivasertib arm and in 85% of patients in the control arm. The results are presented here for supplementary information only.
• Side effects – Serious AEs (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint.
• Side effects – Severe AEs
  • With regard to severe AEs, there was a statistically significant difference between the treatment groups, with a disadvantage for capivasertib in combination with fulvestrant.
• Side effects – Discontinuation due to side effects and PRO-CTCAE
  • No information is available as to whether discontinuation due to AEs involved discontinuation of at least one or all active ingredients (INN). As no data on discontinuations broken down by active ingredient (INN) are available, the results are not suitable for a benefit assessment.
  • The PRO-CTCAE questionnaire is not used due to the non-transparent selection process and the non-traceable selection of items for mapping the symptomatic AEs of capivasertib and fulvestrant.
• Side effects – Specific AEs (diarrhoea, maculopapular rash, stomatitis, nausea)
  • For the endpoints diarrhoea, maculopapular rash, stomatitis and nausea, there is a statistically significant disadvantage compared to capivasertib in combination with fulvestrant in each case.
• Side effects
  • Overall, there is a disadvantage for capivasertib in combination with fulvestrant in terms of side effects.
• Overall assessment
  • On balance, the positive effect on overall survival is offset by negative effects in the endpoint categories of morbidity and side effects. On weighing up the evidence, the disadvantages are assessed as not calling into question the extent of the additional benefit resulting from the significant improvement in overall survival.
  • The G-BA concludes that capivasertib in combination with fulvestrant offers a considerable added benefit over fulvestrant alone for the treatment of women with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations, whose disease has progressed during or after endocrine therapy administered at the locally advanced or metastatic stage, there is a considerable additional benefit compared with fulvestrant.
• Level of certainty (probability of additional benefit)
  • In summary, the G-BA derives an indication regarding the established additional benefit based on the level of certainty.

b2) Men with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration(s), with disease progression during or after endocrine therapy administered at the locally advanced or metastatic stage

• The additional benefit is not proven.
• For a direct comparison of capivasertib in combination with fulvestrant against the appropriate comparator therapy, the CAPItello-291 study may in principle be taken into account. However, only two men were included in the intervention arm of the global cohort in this study; consequently, no conclusions regarding additional benefit can be drawn on the basis of this evidence.
• Overall assessment
  • The G-BA therefore concludes that, for capivasertib in combination with fulvestrant for the treatment of men with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration(s), whose disease progressed during or after endocrine therapy administered at the locally advanced or metastatic stage, is not proven to have additional benefit over placebo in combination with fulvestrant.

Courtesy translation only, please refer to the German original.