What is the role of Phosphatidylinositol 3-kinase (PI3K) inhibitors, such as alpelisib (PI3K inhibitor), in the treatment of patients with hormone receptor-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced breast cancer?

PI3K Inhibitors in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Alpelisib (300 mg daily) plus fulvestrant should be offered to patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer after progression on prior endocrine therapy, specifically positioning it after CDK4/6 inhibitor failure rather than as first-line therapy. 1

Patient Selection and Biomarker Testing

PIK3CA mutation testing is mandatory before considering alpelisib therapy. 1

• Use next-generation sequencing on either tumor tissue or circulating tumor DNA (ctDNA) in plasma to detect PIK3CA mutations 1
• If ctDNA testing is negative, reflex to tumor tissue testing, as plasma testing misses approximately 44% of mutations confirmed in tissue (only 56% concordance) 1
• Test the most recent tumor sample available, as PIK3CA mutations can be acquired during metastatic treatment 1
• Specific activating mutations in exons 9 and 20 (E542K, E545X, H1047X) form the basis of regulatory approval 1
• This recommendation applies equally to postmenopausal women and men 1

Treatment Sequencing

The optimal sequence is CDK4/6 inhibitor plus endocrine therapy first-line, followed by alpelisib plus fulvestrant for PIK3CA-mutated tumors after progression. 1

• Alpelisib should be used after CDK4/6 inhibitor therapy, not before, given the superior benefit profile of CDK4/6 inhibitors 1
• The BYLieve trial demonstrated efficacy of alpelisib after CDK4/6 inhibitor progression, with 50.4% of patients alive without progression at 6 months 2
• For PIK3CA wild-type or unknown mutation status after CDK4/6 inhibitor failure, consider everolimus plus exemestane instead 1

Efficacy Data

The SOLAR-1 trial provides the primary evidence base: 1, 3

• Progression-free survival: 11.0 months with alpelisib-fulvestrant versus 5.7 months with placebo-fulvestrant (HR 0.65, P<0.001) in PIK3CA-mutated cohort 1, 3
• Overall survival: 39.3 months versus 31.4 months (7.9 month improvement), but did not meet prespecified statistical significance 1
• No benefit observed in PIK3CA wild-type tumors 1, 3
• Overall response rate: 26.6% versus 12.8% in the alpelisib versus placebo arms 3

Critical Patient Selection Criteria

Careful screening for contraindications is essential due to substantial toxicity. 1

Exclude patients with:

• Pre-existing diabetes or elevated baseline HbA1c 1
• Significant comorbidities that would compromise toxicity management 1

Key considerations:

• Only 6% of SOLAR-1 patients had prior CDK4/6 inhibitor exposure, though subsequent data support use in this setting 1, 2
• Baseline metabolic status impacts outcomes: patients with normal glucose metabolism had longer PFS (12 vs 7.5 months) compared to prediabetic/diabetic patients 4

Toxicity Management

Toxicity is substantial and requires proactive management strategies. 1

Most common grade 3-4 adverse events:

• Hyperglycemia: 36.6% (grade 3: 28-36.6%, grade 4: rare) 1, 3
• Rash: 9.9% grade 3-4 1, 3
• Diarrhea: 6.7% grade 3 1, 3
• Gastrointestinal complaints (nausea, vomiting, mucositis) 1

Management approach:

• Start non-sedating antihistamines prophylactically at treatment initiation to prevent rash; discontinue after 4 weeks as rash risk is highest in first 2 weeks 1
• Dose reductions/interruptions occurred in approximately 70% of patients 1
• Treatment discontinuation due to adverse events: 25% 1
• Close monitoring of glucose levels is mandatory 1

Quality of Life Considerations

Despite significant toxicity, quality of life data from SOLAR-1 showed no overall deterioration in Global Health Status/QoL scores between alpelisib and placebo arms, with no statistically significant difference in time to 10% deterioration 1

Alternative Options

If PIK3CA mutation testing cannot be performed, mutation is wild-type, or alpelisib tolerability is a concern, everolimus plus exemestane remains an option after aromatase inhibitor progression, though no direct comparison data exist between alpelisib and everolimus 1