What are the next treatment options for squamous skin cancer with progression on Libtayo (cemiplimab) after chemo-radiation?

Treatment Options After Cemiplimab Progression in Advanced Cutaneous Squamous Cell Carcinoma

For advanced cutaneous squamous cell carcinoma progressing on cemiplimab after prior chemoradiation, consider alternative immunotherapy with pembrolizumab, combination approaches with radiation therapy, or EGFR inhibitors like cetuximab, while recognizing that evidence for this specific sequence is limited and outcomes are generally poor.

Primary Treatment Considerations

Alternative Immunotherapy

• Pembrolizumab represents a reasonable next option despite limited data on sequencing after cemiplimab failure, as it targets the same PD-1 pathway but may have different binding characteristics 1
• Cross-resistance between PD-1 inhibitors is likely but not absolute, and case reports suggest occasional responses to sequential checkpoint inhibitors 2
• No head-to-head comparisons exist between cemiplimab and pembrolizumab in cutaneous SCC, though both demonstrate activity in treatment-naive advanced disease 1

EGFR-Targeted Therapy

• Cetuximab (an EGFR inhibitor) is indicated for locally or regionally advanced cutaneous squamous cell carcinoma of the head and neck, particularly in combination with radiation therapy or chemotherapy 3
• This represents a mechanistically distinct approach from checkpoint inhibition and may provide benefit after immunotherapy failure 4
• EGFR inhibitors have demonstrated efficacy in metastatic cutaneous SCC, albeit based on limited data 4

Radiation Therapy Integration

• Concurrent radiation therapy with systemic therapy should be strongly considered for locoregional disease, as it provides direct local tumor control and may enhance systemic treatment efficacy 5
• Radiation combined with cemiplimab showed earlier clinical response (3 months vs 5.5 months for cemiplimab alone) and provided therapeutic benefit in 83.3% of patients without increasing adverse events 5
• For progression on cemiplimab, radiation to new or progressive sites combined with alternative systemic therapy may provide palliative benefit 4

Surgical Considerations

Reassessment for Surgical Resection

• Regional lymph node dissection remains the preferred treatment if nodal disease is present and surgically resectable, even after systemic therapy failure 4, 3
• Complete surgical excision should be reconsidered if disease has become technically resectable, as incomplete excision is associated with poor prognosis 3
• For parotid involvement, superficial parotidectomy should be performed if the cancer extends into the parotid parenchyma, as disease-specific survival is inferior with radiation alone 4

Chemotherapy Options

Platinum-Based Regimens

• Cisplatin as a single agent or in combination therapy may be considered for metastatic disease, though data are limited 4
• Combination chemoradiation therapy should be considered for inoperable disease, particularly with concurrent cisplatin for patients with extracapsular extension or microscopically involved surgical margins 4
• Two randomized trials in mucosal squamous cell tumors showed superior locoregional control and progression-free survival with postoperative radiation plus concurrent cisplatin compared with radiation alone 4

Clinical Factors Predicting Poor Response

Negative Prognostic Indicators

Several factors identified in real-world cemiplimab data suggest worse outcomes and should inform treatment intensity decisions:

• Performance status ≥1 is significantly associated with worse response (p = 0.012) 6
• Genital location of primary tumor correlates with poor response (p = 0.041) 6
• Previous chemotherapy is associated with worse outcomes (p = 0.0020) 6
• Chronic corticosteroid therapy predicts poor response (p = 0.038) 6
• Systemic antibiotic use within 1 month of treatment initiation correlates with worse response (p = 0.012) 6
• Anemia (hemoglobin below normal range) is associated with poor response (p = 0.034) 6

Best Supportive Care

Palliative Approach

• Patients with advanced disease should be provided with or referred for best supportive and palliative care to optimize symptom management and maximize quality of life 4
• For patients with performance status 3-4, palliative care/best supportive care is recommended over aggressive systemic therapy 4
• Despite resection followed by radiation therapy, high-risk patients experience locoregional recurrence rates of 30%, distant metastasis rates of 25%, and 5-year survival rates of only 40% 4

Critical Caveats

The evidence base for treatment after cemiplimab progression is extremely limited, as cemiplimab is the only FDA-approved agent specifically for advanced cutaneous SCC 7, 1. Most available data comes from lung cancer squamous cell carcinoma, which has different biology and treatment paradigms 4.

Multidisciplinary consultation is strongly recommended for patients with locoregional or distant metastases, particularly in immunosuppressed individuals who have 2- to 3-fold increased risk of metastasis 3. Clinical trial enrollment should be actively pursued when available, as standard options are limited and outcomes are poor 4.