Is Focinvez (Aprepitant) covered for prevention of chemotherapy-induced nausea and vomiting in a patient receiving trastuzumab deruxtecan (Trastuzumab and Deruxtecan)?

Coverage Decision for Focinvez (Fosaprepitant) for Trastuzumab Deruxtecan-Induced Nausea and Vomiting

Approve coverage for Focinvez (fosaprepitant) as part of triple antiemetic therapy for this patient receiving trastuzumab deruxtecan, as this agent requires neurokinin-1 receptor antagonist prophylaxis based on its high emetogenic potential from the deruxtecan component.

Rationale for Coverage

Emetogenic Classification of Trastuzumab Deruxtecan

• Trastuzumab deruxtecan is an antibody-drug conjugate containing deruxtecan (DXd), a topoisomerase I inhibitor chemotherapy component that confers moderate-to-high emetogenic risk 1
• The NCCN guideline version 1.2023 reclassified trastuzumab deruxtecan from moderate to high emetic risk, recommending triple therapy including an NK1 receptor antagonist 1
• While the trastuzumab component itself is not emetogenic, the deruxtecan chemotherapy payload drives the need for aggressive antiemetic prophylaxis 1

Evidence Supporting NK1 Antagonist Use

• A 2023 randomized phase 2 study directly comparing doublet (5-HT3RA + dexamethasone) versus triplet therapy (adding aprepitant/fosaprepitant) for trastuzumab deruxtecan showed significantly superior complete response rates with triple therapy: 70.0% vs 36.8% (P = 0.0190) 1
• The study concluded that patients receiving trastuzumab deruxtecan require triple therapy with mandatory NK1RA administration 1
• The addition of NK1 antagonists to standard therapy provides significantly increased protection from delayed emesis and nausea in patients receiving emetogenic chemotherapy 2

FDA-Approved Indications Met

Fosaprepitant is FDA-approved for:

• Prevention of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy 2
• Prevention of delayed nausea and vomiting associated with moderately emetogenic chemotherapy 2
• Given trastuzumab deruxtecan's reclassification to high emetic risk, this indication is clearly met 1

Recommended Antiemetic Regimen

Day 1 (Before Trastuzumab Deruxtecan)

• Fosaprepitant 115 mg IV (or 150 mg IV single-dose alternative) 2, 3
• Dexamethasone 12 mg PO or IV (reduced from 20 mg due to aprepitant interaction via CYP3A4) 2, 3
• 5-HT3 antagonist: Palonosetron 0.25 mg IV preferred, or granisetron 1 mg IV, or ondansetron 8-12 mg IV 2, 3

Days 2-3 (Post-Chemotherapy)

• If using standard fosaprepitant 115 mg: Aprepitant 80 mg PO on days 2-3 2, 3
• If using high-dose fosaprepitant 150 mg: No additional aprepitant needed on days 2-3 2
• Dexamethasone 8 mg PO or IV daily (or 8 mg twice daily on days 3-4 if using 150 mg fosaprepitant) 2, 3

Clinical Considerations

Drug Interactions

• Aprepitant/fosaprepitant is a CYP3A4 substrate, moderate inducer, and moderate inhibitor 2
• Reduce dexamethasone dose to 50% when combining with aprepitant due to CYP3A4 interaction 2, 3
• Contraindicated with pimozide, terfenadine, astemizole, or cisapride due to risk of serious reactions 2

Common Pitfalls to Avoid

• Do not use doublet therapy alone for trastuzumab deruxtecan - the phase 2 study demonstrated inadequate control with only 36.8% complete response 1
• Do not skip delayed phase prophylaxis - trastuzumab deruxtecan causes significant delayed nausea and vomiting beyond 24 hours 1
• Ensure prophylactic administration 30-60 minutes before chemotherapy rather than waiting for symptoms to develop 2, 3

Safety Profile

• No grade 3 or 4 toxicity related to triple antiemetic therapy was observed in the trastuzumab deruxtecan study 1
• NK1 antagonists are well-tolerated when used according to guideline recommendations 2

Coverage Determination

This request meets criteria for approval because:

1. The medication is FDA-approved for prevention of chemotherapy-induced nausea and vomiting with moderately and highly emetogenic chemotherapy 2
2. Trastuzumab deruxtecan is now classified as high emetic risk by NCCN guidelines 1
3. Level 1 evidence from a 2023 randomized trial demonstrates superior efficacy of triple therapy including NK1 antagonist for this specific agent 1
4. The patient is not pregnant (per exclusion criteria) 2