What is the use and dosage of Capivsertib (investigational drug) in patients with advanced or metastatic cancer?

Capivasertib: Use and Dosage in Advanced or Metastatic Cancer

Capivasertib is FDA-approved at 400 mg orally twice daily for 4 days followed by 3 days off, in combination with fulvestrant, specifically for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with PIK3CA, AKT1, or PTEN alterations after progression on at least one endocrine-based regimen. 1

FDA-Approved Indication and Patient Selection

• Biomarker testing is mandatory: Patients must have tumor tissue demonstrating one or more genetic alterations in PIK3CA, AKT1, or PTEN detected by an FDA-approved test before initiating capivasertib 1, 2
• The approved population includes patients who progressed on at least one endocrine therapy in the metastatic setting OR recurred within 12 months of completing adjuvant therapy 1, 2
• Do not use capivasertib in biomarker-negative patients: The FDA approval specifically excludes patients without PIK3CA/AKT1/PTEN alterations, as exploratory analysis showed uncertain benefit (HR 0.78,95% CI 0.60-1.01) with unfavorable benefit-risk assessment 2

Standard Dosing Regimen

• Recommended dose: 400 mg orally twice daily for 4 consecutive days, followed by 3 days off treatment, repeated weekly in combination with fulvestrant 500 mg intramuscularly 1, 3
• Capivasertib may be taken with or without food 1
• Fulvestrant dosing follows standard protocol: 500 mg intramuscularly on day 1 of each 28-day cycle, with a loading dose on day 15 of cycle 1 3
• Continue treatment until disease progression, unacceptable toxicity, or patient withdrawal 3

Efficacy Data Supporting Approval

• In the biomarker-positive population (PIK3CA/AKT1/PTEN alterations), capivasertib plus fulvestrant demonstrated median progression-free survival of 7.3 months versus 3.1 months with placebo plus fulvestrant (HR 0.50,95% CI 0.37-0.68) 2
• The overall population showed median PFS of 10.3 months with capivasertib versus 4.8 months with placebo (HR 0.58,95% CI 0.39-0.84) 3
• Critical distinction: The PFS benefit was statistically significant and clinically meaningful only in patients with documented PIK3CA/AKT1/PTEN alterations 2

Toxicity Management

Most common adverse reactions requiring monitoring:

• Diarrhea: Occurs in 72% of patients (9% grade ≥3); manage with antidiarrheals and dose modifications as needed 2
• Cutaneous toxicity: Affects 58% of patients (17% grade ≥3), including rash; may require dermatologic consultation and dose adjustments 2
• Hyperglycemia: Occurs in 18% of patients (2.8% grade ≥3); monitor blood glucose regularly, especially in diabetic patients 2
• Hypertension: Reported in 32% of capivasertib-treated patients (grade 3-4); requires blood pressure monitoring and antihypertensive management 3
• Fatigue, nausea, and vomiting: Common but typically manageable with supportive care 2, 4

Investigational Uses Beyond FDA Approval

• Meningiomas with AKT1 p.E17K mutations: Capivasertib showed activity across tumor types harboring AKT1 p.E17K mutations in multihistology basket studies, though this remains investigational 5
• AKT1 p.E17K mutations occur in approximately 10% of meningiomas, typically WHO grade 1 anterior or middle skull base location 5
• Metastatic castration-resistant prostate cancer: Phase 2 ProCAID trial showed median OS of 25.3 months with capivasertib plus docetaxel versus 20.3 months with placebo plus docetaxel (HR 0.70), particularly in patients previously treated with abiraterone/enzalutamide (median OS 25.0 vs 17.6 months; HR 0.57) 6
• These indications remain investigational and should only be considered within clinical trials 5, 6

Key Clinical Pitfalls to Avoid

• Never initiate capivasertib without documented PIK3CA/AKT1/PTEN alterations in breast cancer patients, as the FDA approval is biomarker-restricted and benefit-risk is unfavorable in biomarker-negative patients 2
• Do not continue treatment beyond progression without clear clinical benefit, as no overall survival detriment was observed but efficacy diminishes after progression 2
• Monitor for acute kidney injury, which occurred in two patients as a serious adverse reaction in clinical trials 3
• Be aware of the intermittent dosing schedule (4 days on, 3 days off) to optimize adherence and minimize toxicity 4
• Ensure patients understand the twice-daily dosing requirement and the importance of maintaining the treatment schedule 1, 4