Imlunestrant (1) – Inluriyo®

• Clinical trials
  • In the ongoing three-arm EMBER-3 trial, imlunestrant (arm A) is being compared with fulvestrant or exemestane (arm B) and with imlunestrant in combination with abemaciclib (arm C), although the arm involving Imlunestrant in combination with Abemaciclib was only added retrospectively via a protocol amendment.

a1) Women with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following (neo-)adjuvant endocrine therapy; no previous treatment at the locally advanced or metastatic stage

• Overall, there is neither a benefit nor a disadvantage in terms of overall survival.
• No suitable data are available for the other endpoint categories.
• For patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following (neo-)adjuvant endocrine therapy and who have not previously received treatment at the locally advanced or metastatic stage, additional benefit is not proven with imlunestrant compared with endocrine therapy using either fulvestrant or exemestane.
• mortality
  • The endpoint of overall survival was defined in the EMBER-3 trial as the time from randomisation to death from any cause. No statistically significant difference was observed between the trial arms.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is the primary endpoint of the EMBER-3 trial. It is defined as the time from randomisation to the first documented disease progression or death from any cause in the absence of disease progression.
  • A statistically significant advantage in favour of imlunestrant was observed for PFS as assessed by both the BICR and the investigator.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (EORTC QLQ-C30, symptom scales)
  • Symptoms were assessed in the EMBER-3 study using the symptom scales of the EORTC QLQ-C30 questionnaire.
  • Due to the minor number of patients at baseline and the sharp decline in questionnaire response rates at a very early stage, the results are unsuitable and will not be taken into account for the assessment.
• Morbidity – Most severe pain (BPI-SF Item 3)
  • The endpoint ‘worst pain’ was assessed using item 3 of the BPI-SF.
  • Due to the minor number of patients at baseline and the sharp decline in questionnaire response rates at a very early stage, the results are unsuitable and are not included in the assessment.
• Morbidity – Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • Due to the minor number of patients at baseline and the sharp decline in questionnaire response rates very early on, the results are not suitable and are not included in the assessment.
• Health-related quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed in the EMBER-3 study using the functional scales of the EORTC QLQ-C30 questionnaire.
  • Due to the minor number of patients at baseline and the sharp decline in questionnaire response rates very early on, the results are not suitable and are not included in the assessment.
• Side effects – AEs, severe AEs (CTCAE grade ≥ 3), discontinuation due to AEs
  • Due to the major limitations described above regarding the collection of adverse events in the EMBER-3 study, the data are generally unsuitable for the quantitative assessment of the benefit of imlunestrant compared with the comparator therapy.
• Side effects – PRO-CTCAE
  • In accordance with the EMBER-3 study protocol, two symptomatic adverse events were recorded from the PRO-CTCAE system: diarrhoea, and pain and swelling at the injection site.
  • Due to the lack of transparency in the selection process for symptomatic AEs, the PRO-CTCAE questionnaire is not used for the benefit assessment.
• Overall assessment/Conclusion
  • For the assessment of the additional benefit of imlunestrant in patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following (neo-)adjuvant endocrine therapy and who have not previously received treatment at the locally advanced or metastatic stage, results on mortality, morbidity, health-related quality of life and side effects are available from the randomised, controlled EMBER-3 trial.
  • For this patient population from the EMBER-3 trial, only the endpoint of overall survival yields usable results, which show no statistically significant difference between the treatment groups.
  • The results for the patient-reported endpoints relating to symptoms (EORTC QLQ-C30, symptom scales), most severe pain (BPI-SF Item 3) and health status (EQ-5D VAS), as well as on health-related quality of life (EORTC QLQ-C30, functional scales) are not analysable due to response rates falling sharply at a very early stage and the fact that significant proportions of patients were excluded from the analysis (approximately 22 to 32 per cent depending on the endpoint).
  • Due to the major limitations in the collection of adverse events (AEs) in the EMBER-3 study, the data on side effects are generally unsuitable for a quantitative assessment of the benefit of imlunestrant compared with the comparator therapy.
  • Due to the very small number of patients (30 vs. 23 patients) and the limited number of valid analyses from the EMBER-3 study, only very limited conclusions can be drawn regarding first-line treatment in this therapeutic indication.

a2) Men with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following (neo-)adjuvant endocrine therapy; no previous treatment at the locally advanced or metastatic stage

• The pharmaceutical manufacturer has not provided any data for men to assess the additional benefit of imlunestrant compared with the appropriate comparator therapy.
• The G-BA therefore concludes that, for imlunestrant in men with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following (neo-)adjuvant endocrine therapy and who have not previously received treatment at the locally advanced or metastatic stage, an additional benefit is not proven.

b1) Women with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following endocrine therapy administered at the locally advanced or metastatic stage

• Overall, there is a clear improvement in the endpoint of overall survival.
• No suitable data are available for the other patient-relevant endpoints.
• The data on side effects are, on the whole, unsuitable for a quantitative assessment of the benefit of imlunestrant compared with the comparator therapy, due to the relevant limitations in the recording of adverse events (AEs) in the EMBER-3 study.
• However, taking into account the findings in the EMA’s EPAR and the statements from professional societies regarding the side effects of imlunestrant, it is not considered that these side effects call into question the advantage in terms of overall survival. Nevertheless, weighing up the benefits and harms of imlunestrant is significantly more difficult.
• On balance, it is not possible to quantify the additional benefit due to the available data, which is, on the whole, very limited.
• Consequently, for patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following endocrine therapy administered at the locally advanced or metastatic stage, an additional benefit has been identified for Imlunestrant compared with endocrine therapy using either fulvestrant or exemestane, which cannot be quantified.
• The certainty of the evidence for the identified additional benefit is classified as ‘hint’.
• mortality
  • The endpoint of overall survival was defined in the EMBER-3 study as the time from randomisation to death from any cause. A statistically significant advantage was observed in favour of Imlunestrant compared with Fulvestrant. The extent of the prolongation in overall survival achieved is considered a marked improvement.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is the primary endpoint of the EMBER-3 study. It is defined as the time from randomisation to the first documented disease progression or death from any cause in the absence of disease progression.
  • For PFS as assessed by the BICR, there is no statistically significant difference, whilst for PFS as assessed by the investigator, there is a statistically significant advantage in favour of imlunestrant.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint.
• Morbidity – Symptoms (EORTC QLQ-C30, symptom scales)
  • Symptoms were assessed in the EMBER-3 study using the symptom scales of the EORTC QLQ-C30 questionnaire.
  • Due to the sharp decline in questionnaire response rates at a very early stage, the results are unsuitable and will not be used for the assessment.
• Morbidity – Most severe pain (BPI-SF Item 3)
  • The endpoint ‘worst pain’ was assessed using item 3 of the BPI-SF.
  • Due to the sharp decline in response rates for the questionnaire at a very early stage, the results are not suitable and are not included in the assessment.
• Morbidity – Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • Due to the sharp decline in questionnaire response rates at a very early stage, the results are not suitable and are not taken into account in the assessment.
• Health-related quality of life – EORTC QLQ-C30
  • Health-related quality of life was assessed in the EMBER-3 study using the functional scales of the EORTC QLQ-C30 questionnaire.
  • Due to the sharp decline in questionnaire response rates at a very early stage, the results are unsuitable and are not included in the assessment.
• Side effects – SUEs, severe adverse events (CTCAE grade ≥ 3), discontinuation due to adverse events
  • Due to the relevant limitations in the collection of adverse events (AEs) in the EMBER-3 study, the data on side effects are generally not suitable for the quantitative assessment of the benefits of imlunestrant compared with the comparator therapy.
• Side effects – PRO-CTCAE
  • In accordance with the EMBER-3 study protocol, two symptomatic AEs were recorded from the PRO-CTCAE system: diarrhoea, and pain and swelling at the injection site.
  • Due to the lack of transparency in the selection process for symptomatic AEs, the PRO-CTCAE questionnaire is not used for benefit assessment.
• Overall assessment/Conclusion
  • For the assessment of the additional benefit of imlunestrant in patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following endocrine therapy administered at the locally advanced or metastatic stage, results are available on mortality, morbidity, health-related quality of life and side effects from the EMBER-3 trial.
  • For this patient population from the EMBER-3 study, usable results are available only for the endpoint of overall survival.
  • The results for the patient-reported endpoints of symptoms (EORTC QLQ-C30, symptom scales), most severe pain (BPI-SF Item 3) and health status (EQ-5D VAS), as well as on health-related quality of life (EORTC QLQ-C30, functional scales) are not usable due to response rates dropping sharply at a very early stage and the fact that significant proportions of patients are excluded from the analysis (20 to 37 per cent depending on the endpoint).

b2) Men with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following endocrine therapy administered at the locally advanced or metastatic stage

• The pharmaceutical manufacturer has not provided any data for men to assess the additional benefit of imlunestrant compared with the appropriate comparator therapy.
• The G-BA therefore concludes that, for imlunestrant in men with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, whose disease has progressed following endocrine therapy administered at the locally advanced or metastatic stage, does not have an additional benefit proven.

Courtesy translation only, please refer to the German original.