Is enfortumab vedotin approved for head‑and‑neck squamous cell carcinoma, and what are its dosing, trial eligibility criteria, and alternative treatment options?

Enfortumab Vedotin is NOT FDA-Approved for Head and Neck Squamous Cell Carcinoma

Enfortumab vedotin (PADCEV) is currently only FDA-approved for urothelial carcinoma, not for head and neck squamous cell carcinoma (HNSCC). The FDA labeling 1 makes no mention of HNSCC as an approved indication. While early phase II data shows promise, this remains an investigational use only.

Current FDA-Approved Status

Enfortumab vedotin is approved exclusively for:

• Locally advanced or metastatic urothelial carcinoma after prior platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy 2
• Available as 20 mg and 30 mg single-dose vials requiring reconstitution and dilution for IV infusion 1

Investigational Data in HNSCC

The EV-202 phase II trial 3 evaluated enfortumab vedotin in heavily pretreated HNSCC patients:

Dosing regimen tested:

• 1.25 mg/kg IV on days 1,8, and 15 of each 28-day cycle

Trial eligibility criteria:

• Recurrent/metastatic HNSCC
• Prior platinum-based therapy for locally advanced/metastatic disease
• Prior PD-1/PD-L1 inhibitor therapy
• Most patients (52.2%) had ≥3 prior lines of systemic therapy

Efficacy results (n=46, median follow-up 9.3 months):

• Confirmed objective response rate: 23.9%
• Disease control rate: 56.5%
• Median progression-free survival: 3.9 months
• Median overall survival: 6.0 months
• Median duration of response: not reached (9.4 months at later cutoff)

Safety profile:

• Treatment-related adverse events in >20%: alopecia (28.3%), fatigue (26.1%), peripheral sensory neuropathy (23.9%)
• Grade ≥3 treatment-related adverse events: 34.8%
• No new safety signals beyond known urothelial carcinoma experience

Biological Rationale

Nectin-4 expression is widespread in HNSCC 4:

• Found in 86.2% of HNSCC cases
• Medium/high expression in 32.7%
• Higher expression in non-smokers and p16-positive (HPV-associated) tumors
• This provides mechanistic justification for targeting nectin-4 in HNSCC, similar to urothelial carcinoma

Current Standard Treatment Options for Recurrent/Metastatic HNSCC

First-line therapy:

• Pembrolizumab monotherapy or pembrolizumab plus chemotherapy for PD-L1 positive disease (Combined Positive Score ≥1)
• Nivolumab is FDA-approved with Category 1 evidence for platinum-refractory disease 5
• Pembrolizumab has Category 2A recommendation 5

Second-line therapy after platinum and immunotherapy failure:

• Single-agent chemotherapy (docetaxel, paclitaxel, methotrexate, or cetuximab) 5
• Clinical trial enrollment strongly encouraged

Clinical Implications

For patients who have exhausted standard options:

• Enfortumab vedotin should only be accessed through clinical trials or expanded access programs
• The 23.9% response rate in heavily pretreated patients 3 is clinically meaningful but does not justify off-label use outside of trials
• Ongoing phase III trials are needed to establish efficacy compared to standard chemotherapy 6

Common pitfalls to avoid:

• Do not prescribe enfortumab vedotin off-label for HNSCC based solely on phase II data
• Insurance will not cover this indication as it lacks FDA approval
• The drug is expensive and toxicity profile includes peripheral neuropathy, which can be cumulative

Alternative emerging options under investigation 6:

• Bispecific antibodies
• HPV-directed therapeutic vaccines (for HPV-positive disease)
• Other antibody-drug conjugates (DS-7300)
• Combination strategies with novel immunotherapy agents

The appropriate approach for platinum and immunotherapy-refractory HNSCC remains enrollment in clinical trials or standard single-agent chemotherapy 5. Enfortumab vedotin represents a promising future option pending completion of phase III trials, but cannot be recommended for routine clinical use at this time.