Alpelisib (1) – Piqray®

• Clinical trials
  • To demonstrate the additional benefit of alpelisib in combination with fulvestrant compared with fulvestrant alone, the pharmaceutical manufacturer has submitted results from the randomised, double-blind, controlled Phase III SOLAR-1 trial.
  • This multinational trial included postmenopausal women and men with HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

a1) Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation, following disease progression after endocrine therapy as monotherapy administered in the (neo-)adjuvant setting; There are no lung and/or liver metastases

• Overall, therefore, there is an indication of less benefit for alpelisib in combination with fulvestrant.
• The certainty of the evidence for the less benefit identified in the overall assessment is classified as an ‘indication’ when viewed in the overall context.
• mortality
  • In the patient population of patients without lung and/or liver metastases, there is no statistically significant difference in overall survival.
  • An additional benefit is therefore not proven for this patient population.
• Morbidity – Symptoms
  • For postmenopausal patients who had received endocrine therapy as part of neo-(adjuvant) treatment, a statistically significant difference to the detriment of alpelisib in combination with fulvestrant was observed for the symptom scales ‘nausea and vomiting’, ‘loss of appetite’ and ‘diarrhoea’ showed a significant disadvantage compared to alpelisib in combination with fulvestrant.
  • For the symptom scales ‘fatigue’, ‘insomnia’, ‘pain’ and ‘constipation’, no significant difference was observed between the treatment groups.
  • Overall, therefore, there is a disadvantage for alpelisib in combination with fulvestrant in terms of symptoms.
• Morbidity – Pain (BPI-SF)
  • For postmenopausal patients who had received endocrine therapy in a neo-(adjuvant) setting, no significant difference was observed between the treatment groups on the ‘most severe pain’ scale.
  • No usable data are available for the ‘pain intensity’ and ‘impairment due to pain’ scales.
  • Overall, therefore, there is no advantage or disadvantage for alpelisib in combination with fulvestrant with regard to the pain endpoint.
• Morbidity – Health status (EQ-5D VAS)
  • For postmenopausal patients who received endocrine therapy in the neo-(adjuvant) setting, no significant difference was observed between the treatment groups.
• quality of life
  • For postmenopausal patients who received endocrine therapy in the neo-(adjuvant) setting, alpelisib in combination with fulvestrant had a significant disadvantage in terms of the ‘social functioning’ subscale.
  • No significant difference was observed between the treatment groups for the ‘physical functioning’, ‘role functioning’, ‘emotional functioning’ and ‘cognitive functioning’ scales, or for overall health status.
  • In the quality of life category, therefore, a disadvantage for alpelisib in combination with fulvestrant can be observed overall.
• Side effects
  • In the SOLAR-1 study, 100.0% of postmenopausal patients in the intervention arm who received endocrine therapy in the neo-(adjuvant) setting experienced an adverse event. In the control arm, the figure was 92.1% of patients.
  • For serious adverse events, a statistically significant difference was observed to the disadvantage of alpelisib in combination with fulvestrant.
  • With regard to the time to onset of severe adverse events of CTCAE grade ≥ 3, a statistically significant difference was observed between the treatment groups, to the detriment of alpelisib in combination with fulvestrant.
  • A statistically significant difference was observed for the median time to therapy discontinuation due to an AE, with a disadvantage for alpelisib in combination with fulvestrant.
  • A detailed analysis of specific adverse events shows that the time to onset of the specific adverse events ‘severe hyperglycaemia’ (SMQ, severe AEs) and ‘severe rash’ (CMQ, severe AEs) was significantly shorter in patients in the intervention arm than in the control arm.
  • Similarly, for the other specific AEs – ‘dysgeusia’ (PT, AEs), ‘alopecia’ (PT, AEs), ‘gastrointestinal disorders’ (SOC, AEs), ‘mucositis’ (PT, AEs), “peripheral oedema” (PT, severe AEs), “diarrhoea” (PT, severe AEs), “hypertension” (PT, severe AEs), “weight loss” (PT, AEs) and ‘Metabolic and nutritional disorders’ (SOC, severe AEs), a statistically significant disadvantage was observed for alpelisib in combination with fulvestrant compared with fulvestrant alone.
  • For the endpoint ‘elevated gamma-glutamyltransferase’ (PT, severe AEs), there was a statistically significant advantage for alpelisib in combination with fulvestrant.
  • In the overall analysis of the side effect endpoints, there were almost exclusively statistically significant disadvantages associated with alpelisib in combination with fulvestrant. Overall, a significant disadvantage was identified for treatment with alpelisib in combination with fulvestrant.
• Overall assessment
  • For patients without lung and/or liver metastases (patient population a1), there is no statistically significant difference in overall survival. An additional benefit in terms of overall survival is therefore not proven for this patient population.
  • The endpoints relating to symptoms, quality of life and side effects show exclusively negative effects. Overall, a significant disadvantage of treatment with alpelisib in combination with fulvestrant compared with fulvestrant alone is identified with regard to side effects.
  • For the reasons stated, it can therefore reasonably be concluded that alpelisib in combination with fulvestrant is not recommended for the patient population of postmenopausal women with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation, following disease progression after endocrine therapy as monotherapy, which was administered in the (neo-)adjuvant setting, and in whom there are no lung and/or liver metastases, offers less benefit than the appropriate comparator therapy.

a2) Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation following disease progression after endocrine therapy as monotherapy, administered in the (neo-)adjuvant setting; Lung and/or liver metastases are present

• The additional benefit is not proven.
• mortality
  • Patients with lung and/or liver metastases treated with alpelisib + fulvestrant showed a statistically significant prolongation in survival time compared with fulvestrant alone (median survival time 40.6 months versus 22.2 months).
  • In contrast, no statistically significant difference was observed in the patient population of patients without lung and/or liver metastases.
  • In the patient population of patients with lung and/or liver metastases, there was a statistically significant prolongation in overall survival, which is assessed as a relevant improvement, although its extent is non-quantifiable.
• Morbidity – Symptoms
  • For postmenopausal patients who received endocrine therapy as part of neo-(adjuvant) treatment, there was a significant difference to the detriment of alpelisib in combination with fulvestrant on the symptom scales ‘nausea and vomiting’, ‘loss of appetite’ and ‘diarrhoea’ each showed a significant disadvantage compared to alpelisib in combination with fulvestrant.
• Morbidity – Pain (BPI-SF)
  • For postmenopausal patients who received endocrine therapy in a neo-(adjuvant) setting, no significant difference was observed between the treatment groups on the ‘most severe pain’ scale.
• Morbidity – Health status (EQ-5D VAS)
  • For postmenopausal patients who received endocrine therapy in a neo-(adjuvant) setting, no significant difference was observed between the treatment groups.
• quality of life
  • For postmenopausal patients who received endocrine therapy as part of neo-(adjuvant) treatment, there was a significant effect in favor of alpelisib in combination with fulvestrant on the ‘social functioning’ subscale.
• Side effects
  • In the overall analysis of the endpoints relating to side effects, there were almost exclusively statistically significant disadvantages associated with alpelisib in combination with fulvestrant. Overall, a significant disadvantage was observed for treatment with alpelisib in combination with fulvestrant.
  • With regard to the specific adverse event (AE) category ‘gastrointestinal disorders’ (SOC, AEs), there is an effect modification in relation to the characteristics ‘lung and/or liver metastases’ and ‘visceral metastases’. Accordingly, the disadvantage is more pronounced in patients with ‘lung and/or liver metastases’ or ‘visceral metastases’.
• Overall assessment
  • For patients with lung and/or liver metastases (patient population a2), there is a statistically significant prolongation of overall survival, which is assessed as a relevant improvement, although its extent is non-quantifiable.
  • This advantage is offset exclusively by negative side effects in the endpoints relating to symptoms, quality of life and side effects. In terms of side effects, a significant disadvantage of treatment with alpelisib in combination with fulvestrant compared with fulvestrant alone is observed overall.
  • In its cost-benefit assessment, the G-BA concludes that, in this case, the advantage in terms of overall survival does not, on balance, outweigh the disadvantages. Consequently, for the patient population of postmenopausal women with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation following disease progression after endocrine therapy as monotherapy, which took place in the (neo-)adjuvant setting, and who have lung and/or liver metastases, it is concluded that an additional benefit is not proven.

a3) Men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation following disease progression after endocrine therapy as monotherapy, administered in the (neo-)adjuvant setting

• The additional benefit is not proven.
• No data are available to assess the additional benefit of alpelisib in combination with fulvestrant compared with the appropriate comparator therapy in men who have received endocrine therapy in the (neo-)adjuvant setting.
• The characterisation of the study population shows that only one man was included in the SOLAR-1 study. Consequently, there is insufficient data to assess the additional benefit.

b1) Postmenopausal women with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation following disease progression after endocrine therapy as monotherapy, administered at the locally advanced or metastatic stage

• Overall, therefore, there is an indication of less benefit for alpelisib in combination with fulvestrant.
• The certainty of the evidence for the less benefit identified in the overall assessment is classified as ‘indication’ in the overall review.
• mortality
  • There is no statistically significant difference between the two treatment arms. The median survival time was 37.2 months with alpelisib in combination with fulvestrant and 31.2 months with fulvestrant alone.
  • For the endpoint of overall survival, an additional benefit of alpelisib in combination with fulvestrant compared with fulvestrant alone is not proven in the present patient population.
• Morbidity – Symptoms
  • For postmenopausal patients who had already received endocrine therapy in the locally advanced or metastatic setting, there was a statistically significant difference to the detriment of alpelisib in combination with fulvestrant for the symptom scales ‘nausea and vomiting’ and ‘diarrhoea’ as well as ‘loss of appetite’, a statistically significant disadvantage was observed for alpelisib in combination with fulvestrant.
  • For the ‘dyspnoea’ symptom scale, a statistically significant advantage was observed in favour of alpelisib plus fulvestrant.
  • For the symptom scales ‘fatigue’, ‘pain’, ‘insomnia’ and ‘constipation’, no significant difference was observed between the treatment groups.
  • In summary, the disadvantages outweigh the advantages, which is why, overall, alpelisib in combination with fulvestrant is associated with a disadvantage in terms of symptoms.
• Morbidity – Pain (BPI-SF)
  • For postmenopausal patients who had already received endocrine therapy in the locally advanced or metastatic setting, no significant difference was observed between the treatment groups on the ‘most severe pain’ scale.
  • No usable data are available for the ‘pain intensity’ and ‘impairment due to pain’ scales.
• quality of life
  • For postmenopausal patients who had already received endocrine therapy in the locally advanced or metastatic setting, a significant effect with a disadvantage for alpelisib in combination with fulvestrant was observed on the ‘social functioning’ scale.
  • No significant difference was observed between the treatment groups for the functional scales ‘physical functioning’, ‘role functioning’, ‘emotional functioning’, ‘cognitive functioning’ and overall health status.
  • In the quality of life category, therefore, a disadvantage for alpelisib in combination with fulvestrant can be observed overall.
• Side effects
  • In the SOLAR-1 trial, 98.7% of postmenopausal patients in the intervention arm who had already received endocrine therapy for locally advanced or metastatic disease experienced an adverse event. In the control arm, the figure was 88.9% of patients.
  • For serious adverse events, a statistically significant difference was observed to the disadvantage of alpelisib in combination with fulvestrant.
  • With regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3, a statistically significant difference was observed between the treatment groups, to the detriment of alpelisib in combination with fulvestrant.
  • A statistically significant difference was observed to the disadvantage of alpelisib in combination with fulvestrant for the median time to therapy discontinuation due to an AE.
  • When examining specific adverse events in detail, the time to onset of the specific adverse events ‘severe hyperglycaemia’ (SMQ, severe AEs) and ‘severe rash’ (CMQ, severe AEs) was significantly shorter in patients in the intervention arm than in the control arm.
  • Similarly, for the other specific AEs ‘alopecia’ (PT, AEs), ‘pruritus’ (PT, AEs), ‘gastrointestinal disorders’ (SOC, AEs), ‘mucosal inflammation’ (PT, AEs), ‘weight loss’ (PT, AEs), ‘stomatitis’ (PT, AEs), ‘musculoskeletal, connective tissue and bone disorders’ (SOC SUEs), ‘Diarrhoea’ (PT, severe AEs), ‘General disorders and administration site conditions’ (SOC, severe AEs), ‘Investigations’ (SOC, severe AEs) and ‘hypokalaemia’ (PT, severe AEs), a statistically significant disadvantage was observed for alpelisib in combination with fulvestrant compared with fulvestrant alone.
  • When the side effect endpoints are considered as a whole, statistically significant disadvantages of alpelisib in combination with fulvestrant are evident across the board. Overall, a significant disadvantage was identified for treatment with alpelisib in combination with fulvestrant.
• Overall assessment
  • For the overall survival endpoint, there was no statistically significant difference between the treatments.
  • In terms of morbidity, a disadvantage was observed with treatment using alpelisib in combination with fulvestrant with regard to the endpoints ‘nausea and vomiting’, ‘diarrhoea’ and ‘loss of appetite’. For the endpoint ‘dyspnoea’, there is an advantage for alpelisib in combination with fulvestrant compared with fulvestrant alone. The disadvantages outweigh the advantage, which is why, overall, there is a disadvantage associated with alpelisib in combination with fulvestrant in terms of symptoms.
  • In the quality of life category, there is a disadvantage associated with alpelisib in combination with fulvestrant with regard to the ‘social functioning’ dimension as assessed using the EORTC QLQ-C30.
  • Statistically significant disadvantages are observed across the board for the endpoints relating to side effects. Overall, a significant disadvantage is identified for the treatment with alpelisib in combination with fulvestrant compared with fulvestrant alone in terms of side effects.
  • Overall, no statistically significant difference in overall survival was observed for alpelisib in combination with fulvestrant, whilst disadvantages were noted in terms of symptoms, quality of life and side effects. In terms of side effects, a significant disadvantage was found overall for treatment with alpelisib in combination with fulvestrant compared with fulvestrant alone.
  • For the reasons stated, it can therefore reasonably be concluded that alpelisib in combination with fulvestrant offers less benefit than the appropriate comparator therapy for postmenopausal women with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA-mutation following disease progression after endocrine therapy as monotherapy, which was administered at the locally advanced or metastatic stage, offers less benefit than the appropriate comparator therapy.

b2) Men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation following disease progression after endocrine therapy as monotherapy, administered at the locally advanced or metastatic stage

• An additional benefit is not proven.
• No data are available to assess the additional benefit of alpelisib in combination with fulvestrant compared with the appropriate comparator therapy in men who have already received endocrine therapy at the locally advanced or metastatic stage.
• The characterisation of the study population shows that only one man was included in the SOLAR-1 trial. Consequently, there is insufficient data to assess the additional benefit.

Courtesy translation only, please refer to the German original.