Does immunotherapy have a role in treating a patient with stage IV non-small cell lung cancer (NSCLC) and skin metastasis?

Immunotherapy is a Standard Treatment for Stage IV NSCLC with Skin Metastasis

Yes, immunotherapy has a central and evidence-based role in treating stage IV non-small cell lung cancer, regardless of metastatic site including skin metastases, and should be offered to all eligible patients with performance status 0-2 without contraindications to immune checkpoint inhibitors. 1

Treatment Selection Algorithm

The treatment approach depends on several key factors that must be assessed systematically:

Step 1: Exclude Oncogenic Drivers

• Molecular testing is mandatory before initiating immunotherapy to exclude EGFR mutations, ALK rearrangements, ROS1, BRAF, RET, MET alterations, and NTRK fusions 2, 3
• Patients with these actionable mutations require targeted therapy first-line, not immunotherapy 3, 4
• Approximately 25% of lung adenocarcinomas harbor EGFR mutations or ALK rearrangements that make targeted therapy superior to immunotherapy 2

Step 2: Assess PD-L1 Expression and Performance Status

• PD-L1 testing using an FDA-approved assay is required to guide treatment selection 1, 4
• Performance status must be 0-1 for combination immunotherapy regimens 1
• Patients with PS 2 may still receive systemic therapy but require special consideration 1

Step 3: Select First-Line Regimen Based on Histology and PD-L1

For Non-Squamous NSCLC:

PD-L1 ≥50%:

• Pembrolizumab monotherapy is the preferred option (median OS 30 vs 14 months compared to chemotherapy) 5
• Alternative: Pembrolizumab + pemetrexed + platinum if combination therapy preferred 1

PD-L1 1-49% or <1%:

• Platinum-based chemotherapy plus PD-1/PD-L1 blockade is the standard approach 1
• Preferred regimens include:
  • Pembrolizumab + pemetrexed + platinum (carboplatin or cisplatin) 1, 3
  • Atezolizumab + bevacizumab + carboplatin + paclitaxel 1, 3
  • Atezolizumab + carboplatin + nab-paclitaxel 1, 4
  • Cemiplimab + platinum-doublet chemotherapy (FDA approved, not EMA approved) 1

For PD-L1 <1% specifically:

• Combination chemo-immunotherapy demonstrates improved overall survival compared to chemotherapy alone 1
• The survival benefit is diminished but still present in PD-L1-negative patients 1, 5

For Squamous NSCLC:

All PD-L1 levels:

• Pembrolizumab + carboplatin + (nab-)paclitaxel is the standard choice (median OS 17.1 vs 11.6 months, HR 0.71) 1, 5
• Benefit observed across all PD-L1 expression levels, though more robust in PD-L1 ≥1% 5
• Alternative: Nivolumab + ipilimumab for squamous histology 1

PD-L1 ≥50%:

• Pembrolizumab monotherapy is an option 5

Step 4: Special Consideration for High Tumor Mutational Burden (TMB)

• For TMB ≥10 mutations/Mb, nivolumab plus ipilimumab is a first-line option regardless of PD-L1 expression 1, 2
• This applies to both squamous and non-squamous histology with PS 0-1 1

Treatment Administration

Duration and monitoring:

• Administer 4 cycles of platinum-based chemotherapy with immunotherapy, followed by immunotherapy maintenance until disease progression or unacceptable toxicity 1
• Response evaluation after 2-3 cycles (6-9 weeks) using the same radiographic modality 1
• Immunotherapy can continue for up to 2 years in the absence of progression 2

Dosing schedules:

• Pembrolizumab: 200 mg every 3 weeks 5
• Atezolizumab: 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks 4
• When combining with chemotherapy, administer immunotherapy prior to chemotherapy when given on the same day 4

Critical Contraindications to Avoid

Absolute contraindications for immune checkpoint inhibitors:

• Active autoimmune disease requiring systemic immunosuppression 4
• Systemic immunosuppressive medications within 2 weeks prior to treatment 4
• Live attenuated vaccines within 28 days 4
• Refer to ESMO guidelines on management of toxicities from immunotherapy for complete list 1

Bevacizumab-specific contraindications:

• Do not use bevacizumab in squamous histology due to risk of life-threatening hemoptysis 5, 3
• Bevacizumab should only be combined with chemotherapy in non-squamous NSCLC 1, 3

When Immunotherapy Cannot Be Used

If contraindications to immunotherapy exist:

• Platinum-based doublet chemotherapy remains the standard 1
• For non-squamous: Pemetrexed + platinum preferred 1
• For squamous: Gemcitabine, vinorelbine, or taxanes + platinum 1
• Bevacizumab may be added to paclitaxel/carboplatin in non-squamous NSCLC (median OS improvement) 1, 3

Skin Metastasis Considerations

The presence of skin metastases does not alter the immunotherapy treatment algorithm 1. The treatment strategy is determined by:

• Histology (squamous vs. non-squamous)
• Molecular profile (presence/absence of oncogenic drivers)
• PD-L1 expression level
• Performance status
• Presence of contraindications to immunotherapy

Skin metastases are simply one manifestation of stage IV disease and do not require modification of systemic therapy approach 1.

Expected Outcomes

Overall survival benefits with immunotherapy combinations:

• Non-squamous with pembrolizumab + chemotherapy: Benefit across all PD-L1 levels 1
• Squamous with pembrolizumab + chemotherapy: Median OS 17.1 vs 11.6 months (HR 0.71) 5
• Atezolizumab + bevacizumab + chemotherapy: Median OS 19.5 vs 14.7 months (HR 0.80) 3
• High TMB with nivolumab + ipilimumab: Higher response rates and potential for durable long-term responses 2