In a patient with unresectable sinonasal squamous cell carcinoma who progressed after first‑line pembrolizumab combined with cisplatin and 5‑fluorouracil, what is the most appropriate next step in management?

Second-Line Treatment for Progressive Sinonasal Squamous Cell Carcinoma

Switch to nivolumab or alternative checkpoint inhibitor monotherapy as the next treatment step, given progression on first-line pembrolizumab-based therapy. 1

Treatment Algorithm After Pembrolizumab/Platinum/5-FU Failure

Primary Recommendation: Alternative Checkpoint Inhibitor

• Nivolumab monotherapy is the preferred second-line option for patients who progressed on pembrolizumab-based first-line therapy, as it represents a different anti-PD-1 agent with demonstrated efficacy in head and neck squamous cell carcinoma after platinum failure 1
• This recommendation extrapolates from ESMO guidelines for recurrent/metastatic head and neck squamous cell carcinoma, which specifically address patients "pretreated with platinum-based chemotherapy within the last 6 months and with prior immunotherapy" 1

Alternative Options Based on Patient Fitness

For fit patients eligible for platinum rechallenge:

• Cetuximab plus platinum/5-FU (EXTREME regimen) can be considered if the patient has good performance status and adequate time has elapsed since last platinum exposure (ideally >6 months, though your patient received it recently) 1
• The EXTREME regimen showed objective response rates of 35.6% in the KEYNOTE-048 trial, providing a chemotherapy-based alternative when immunotherapy has failed 1, 2

For patients unfit for platinum-based therapy:

• Single-agent taxane (docetaxel or paclitaxel) represents a reasonable option with manageable toxicity 1
• Methotrexate monotherapy is an alternative for patients with contraindications to both immunotherapy continuation and platinum-based regimens 1
• Cetuximab monotherapy can be considered, though evidence is limited to level III 1

Critical Considerations for Sinonasal Primary Site

Disease-Specific Context

• While sinonasal squamous cell carcinoma is not specifically addressed in most head and neck cancer guidelines, treatment principles from oral cavity, larynx, oropharynx, and hypopharynx squamous cell carcinoma apply 1
• A recent prospective phase II study demonstrated that pembrolizumab with nab-paclitaxel and platinum achieved 60% objective response rate in first-line recurrent/metastatic sinonasal squamous cell carcinoma, but this does not inform second-line decisions after progression 3

Reassessment for Local Therapy

• Evaluate for oligoprogression or isolated locoregional recurrence that might be amenable to salvage surgery or re-irradiation, particularly if systemic disease burden is low 1
• Patients should be discussed in a multidisciplinary tumor board at a tertiary referral center to determine if any curative-intent local therapy is feasible 1
• If high burden of distant metastases exists (>2 sites, visceral involvement), systemic therapy remains the priority 1

Evidence Gaps and Clinical Pitfalls

Lack of PD-L1 Status Impact on Second-Line Decisions

• Unlike first-line therapy where PD-L1 combined positive score guides pembrolizumab monotherapy decisions, PD-L1 expression does not predict benefit from nivolumab in the second-line setting for head and neck squamous cell carcinoma 1
• The CheckMate 017 study showed nivolumab superiority over docetaxel regardless of PD-L1 expression levels (1%, 5%, or 10% cutoffs) 1

Common Pitfall: Continuing Same Checkpoint Inhibitor

• Do not continue pembrolizumab after clear progression, as this represents treatment failure and switching mechanisms of action is appropriate 1
• While nivolumab is also an anti-PD-1 agent, institutional protocols often support trying an alternative checkpoint inhibitor, and guidelines list both nivolumab and pembrolizumab as options in this setting 1

Timing Considerations

• Since your patient received platinum-based chemotherapy within the last 6 months, rechallenge with platinum/5-FU/cetuximab is technically feasible but may have reduced efficacy and increased cumulative toxicity 1
• The ESMO algorithm specifically categorizes patients as "pretreated with platinum-based chemotherapy within the last 6 months and with prior immunotherapy," for whom nivolumab or pembrolizumab (alternative checkpoint inhibitor) is standard 1

Performance Status and Best Supportive Care

• Performance status 0-2 is required for active systemic therapy; patients with performance status 3-4 should receive best supportive care only 1
• Palliative care consultation should be integrated early to optimize symptom management and quality of life, regardless of whether active treatment is pursued 1