Inavolisib (1) – Itovebi®

• Clinical trials
  • The INAVO120 trial is an ongoing, multicentre, double-blind, randomised, controlled Phase III trial comparing inavolisib in combination with palbociclib and fulvestrant against placebo in combination with palbociclib and fulvestrant.

a1) Women with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following a recurrence during or within 12 months of completing adjuvant endocrine therapy, who have not previously received treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy

• mortality
  • In the INAVO120 study, overall survival is defined as the time from randomisation to death from any cause.
  • A statistically significant difference was observed between the treatment arms, with an advantage for inavolisib, with an extent that is assessed as a marked improvement.
  • The subgroup analysis revealed an effect modification by the characteristic ‘age’. For patients < 65 years of age, a statistically significant advantage was observed in favour of inavolisib, whilst for patients ≥ 65 years of age, no statistically significant difference was observed between the treatment groups.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the INOVA120 study. It is defined as the time from randomisation to the earliest date of the first documented disease progression (defined according to RECIST 1.1 criteria) or death from any cause, whichever occurred first.
  • A statistically significant advantage in favour of inavolisib was observed for PFS.
  • 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 overall survival endpoint. The morbidity component is assessed in accordance with RECIST criteria and thus by means of imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
  • Symptomatic skeletal events
  • The ‘skeletal events’ endpoint in the INAVO120 study is a composite endpoint comprising the individual components of pathological fracture, radiotherapy to the bone, cancer-related surgery on the bone and spinal cord compression.
  • In principle, the endpoint ‘symptomatic skeletal events’ is relevant for the benefit assessment. However, the dossier lacks information on the incidence of the individual sub-components for the INAVO120 study. Furthermore, it is unclear from the available data whether the operationalisation used actually reflects symptomatic skeletal events. Furthermore, in accordance with the study protocol, the use of local radiotherapy is subject to certain conditions or additional consultations, meaning it remains unclear whether all relevant events were included in the analysis.
  • Due to the uncertainties described, the results for the skeletal events endpoint are not taken into account for the assessment.
  • Symptoms
  • EORTC QLQ-C30 and EORTC QLQ-BR23
  • Symptoms were assessed in the INAVO120 study using the symptom scales of the EORTC QLQ-C30 and EORTC QLQ-BR45 questionnaires.
  • As the response rate for the questionnaires was too minor from an early stage and also varied significantly between the treatment arms, the results are unsuitable and will not be used for the evaluation.
  • Most severe pain
  • BPI-SF Item 3
  • The endpoint ‘worst pain’ was assessed using item 3 of the BPI-SF.
  • The pharmaceutical manufacturer does not present any results for this in the dossier because the instrument was administered with an incorrect time frame (7 days instead of 24 hours).
  • However, the data for the BPI-SF questionnaire are not usable, as with the EORTC questionnaires—as already described under ‘Symptoms’—due to the minor response rates at an early stage and the significant differences in response rates between the treatment arms.
  • health status
  • EQ-5D VAS
  • No suitable data on health status, collected using the EQ-5D VAS, are available.
  • Overall, the data on health status are not usable, as the response rates for the EQ-5D VAS were too minor from an early stage and also varied significantly between the treatment arms.
• Health-related quality of life
  • EORTC QLQ-C30 and EORTC QLQ-BR23
  • Health-related quality of life was assessed in the INAVO120 study using the functional scales of the EORTC QLQ-C30 and EORTC QLQ-BR45 questionnaires.
  • As the response rates for the questionnaires are too minor at an early stage and also vary significantly between the treatment arms, the results are unsuitable and are not used for the evaluation.
• Side effects
  • Total adverse events (AEs)
  • In the INAVO120 study, an AE occurred in all patients in both treatment arms. The results are presented for supplementary information only.
  • Serious AEs (SAEs) and severe AEs
  • No statistically significant differences were observed between the treatment groups for the endpoints SAE and severe AEs.
  • Therapy discontinuations due to AEs
  • For the endpoint of discontinuation due to AEs, there was a statistically significant disadvantage for inavolisib in combination with palbociclib and fulvestrant compared with the control arm.
  • Specific AE
  • For the endpoints of stomatitis, hyperglycaemia, reduced appetite, non-infectious diarrhoea, reduced platelet count, metabolic and nutritional disorders, and gastrointestinal disorders, there is a statistically significant disadvantage compared to inavolisib in each case.
  • PRO-CTCAE
  • In accordance with the study protocol, side effects in the INAVO120 study were also recorded using the PRO-CTCAE instrument, specifically seven symptomatic side effects and one item relating to the general burden of side effects. In Module 4, the pharmaceutical manufacturer provides no information on the PRO-CTCAE.
  • Overall, it is not clear on what criteria the items were selected, nor whether side effects of inavolisib, palbociclib or fulvestrant are adequately reflected. Therefore, the PRO-CTCAE endpoint is not used for the assessment.
  • Conclusion on side effects
  • In the ‘side effects’ endpoint category, there are no statistically significant differences between the treatment arms for SAE and severe AEs. For the endpoint ‘therapy discontinuations due to AEs’, there is a disadvantage for inavolisib. In detail, there are disadvantages for the inavolisib combination with regard to specific AEs.
  • In the overall assessment of the results on side effects, a disadvantage is inferred for the ‘side effects’ endpoint category as a whole.

a2) Women with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, following a recurrence during or within 12 months of completing adjuvant endocrine therapy, which included prior treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy

• The G-BA therefore concludes that, for inavolisib in combination with palbociclib and fulvestrant in women with PIK3CA-mutated, oestrogen receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following a recurrence during or within 12 months of completion of adjuvant endocrine therapy and prior treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy, an additional benefit over palbociclib and fulvestrant is not proven.
• mortality
  • The study population of the INAVO120 trial comprises only 3 patients who had previously received treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy. Consequently, there are insufficient data available to assess the additional benefit for this patient population.
• morbidity
  • The study population of the INAVO120 trial comprises only 3 patients who had previously received treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy. Consequently, there are insufficient data to assess the additional benefit for this patient population.
• Health-related quality of life
  • The study population of the INAVO120 trial comprises only 3 patients who have previously received treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy. Consequently, there are insufficient data to assess the additional benefit for this patient population.
• Side effects
  • The study population of the INAVO120 trial comprises only 3 patients who have previously received treatment with a CDK4/6 inhibitor as part of (neo)adjuvant therapy. Consequently, there are insufficient data to assess the additional benefit for this patient population.

b) Men with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following a recurrence during or within 12 months of completing adjuvant endocrine therapy

• The G-BA therefore concludes that, for inavolisib in combination with palbociclib and fulvestrant in men with PIK3CA-mutated, oestrogen receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following a recurrence during or within 12 months of completion of adjuvant endocrine therapy, additional benefit is not proven compared with palbociclib and fulvestrant.
• mortality
  • In the INAVO120 trial, the treatment in the comparator arm does not correspond to the appropriate comparator therapy specified by the G-BA for the patient group of men. Furthermore, only 6 men were included in total. Consequently, there are no suitable data available to assess the additional benefit for this patient population.
• morbidity
  • In the INAVO120 study, the treatment in the comparator arm does not correspond to the appropriate comparator therapy specified by the G-BA for the male patient group. Furthermore, only 6 men were included in total. Consequently, there are no suitable data available to assess the additional benefit for this patient population.
• Health-related quality of life
  • In the INAVO120 study, the treatment in the comparator arm does not correspond to the appropriate comparator therapy specified by the G-BA for the group of male patients. Furthermore, only 6 men in total were included. Consequently, there are no suitable data available to assess the additional benefit for this patient population.
• Side effects
  • In the INAVO120 study, the treatment in the comparator arm does not correspond to the appropriate comparator therapy specified by the G-BA for the male patient group. Furthermore, only 6 men in total were included. Consequently, there are no suitable data available to assess the additional benefit for this patient population.

Courtesy translation only, please refer to the German original.