What is the evidence supporting the use of pembrolizumab (Keytruda) as first-line systemic therapy for metastatic cutaneous squamous cell carcinoma?

Pembrolizumab for Metastatic Cutaneous Squamous Cell Carcinoma

Pembrolizumab is FDA-approved and demonstrates robust efficacy for metastatic cutaneous squamous cell carcinoma (cSCC), with objective response rates of 34-35% and durable responses, making it a first-line systemic therapy option for patients not amenable to surgery or radiation. 1, 2

FDA Approval and Indication

Pembrolizumab received FDA approval in 2020 for recurrent or metastatic cSCC not amenable to curative surgery or radiation 1, 3. The standard dosing is 200 mg intravenously every 3 weeks for up to 35 cycles (approximately 2 years) 1, 4.

Clinical Efficacy Data

Pivotal Trial Evidence (KEYNOTE-629)

The KEYNOTE-629 trial provides the strongest evidence for pembrolizumab in metastatic cSCC 2, 4:

• Objective Response Rate (ORR): 34.3-35.2% in the recurrent/metastatic cohort 2, 4
• Complete Response Rate: 10.5% 4
• Partial Response Rate: 24.8-30.5% 4, 2
• Disease Control Rate: 52.4% 2
• Median Duration of Response: Not reached, indicating durable responses (range 2.7 to 13.1+ months) 2
• Median Progression-Free Survival: 6.9 months 2
• Median Overall Survival: Not reached at median follow-up of 11.4 months 2

Additional Supporting Evidence

A French phase II study (n=39 primary cohort) demonstrated similar efficacy 5:

• ORR at Week 15: 41% (95% CI: 26-58%)
• Best ORR: 41% with 8 complete and 8 partial responses
• Median PFS: 6.7 months
• Median OS: 25.3 months
• Median Duration of Response: Not reached

PD-L1 as a Predictive Biomarker

PD-L1 expression appears predictive of pembrolizumab response in cSCC 5:

• PD-L1 positive patients (≥1% tumor proportion score): 55% ORR
• PD-L1 negative patients: 17% ORR (P = 0.02)

This represents a significant difference, though pembrolizumab can still benefit PD-L1 negative patients. Testing PD-L1 status may help inform treatment discussions but is not required for treatment eligibility 5.

Safety Profile

Pembrolizumab demonstrates a manageable and acceptable safety profile in elderly cSCC patients 2, 4:

• Treatment-related adverse events: 66.7-71% of patients 2, 5
• Grade 3-5 treatment-related adverse events: 5.7-7% 2, 5
• Most common adverse events: pruritus (14.3%), asthenia (13.3%), fatigue (12.4%) 2
• Fatal adverse events: Rare (1 death from cranial nerve neuropathy in KEYNOTE-629; 1 death from rapid disease progression in French study) 2, 5

The safety profile is particularly important given the predominantly elderly patient population (median age 79 years) 5.

Clinical Application Algorithm

For patients with metastatic cSCC:

1. Confirm disease is not amenable to curative surgery or radiation
2. Assess performance status (ECOG 0-1 preferred based on trial eligibility)
3. Exclude contraindications: Active autoimmune disease requiring systemic therapy, medical conditions requiring chronic immunosuppression 1
4. Consider PD-L1 testing to inform response expectations, though not required for treatment
5. Initiate pembrolizumab 200 mg IV every 3 weeks
6. Assess response at Week 9, then every 6 weeks for first year, then every 9 weeks 1
7. Continue treatment until: Disease progression, unacceptable toxicity, or maximum 24 months 1

Important Caveats

Immunocompromised Patients

The evidence base for pembrolizumab in immunocompromised patients (solid organ transplant recipients, chronic immunosuppression) is limited, as these patients were excluded from major trials 1, 3. Use caution and consider multidisciplinary consultation in this population.

Duration of Therapy

While FDA approval allows treatment up to 24 months, the optimal duration remains unclear 1. Some patients achieve complete response and may not require the full 2-year course, but no high-quality data define minimum treatment duration.

Distinguishing Progression from Pseudoprogression

Clinical assessment can be challenging, particularly distinguishing true progression from reactive conditions like erosive pustular dermatosis or pseudoprogression 6. Close clinical monitoring and potential biopsy confirmation may be necessary.

Comparison to Alternative Immunotherapy

While cemiplimab is also FDA-approved for advanced cSCC and shows similar efficacy, pembrolizumab has a broader evidence base across multiple tumor types and established safety profile 7, 3. Both are reasonable first-line options, with choice often determined by availability and institutional experience.