What is the indication for dual Immuno-Oncology (IO) therapy with nivolumab (nivolumab) and ipilimumab (ipilimumab) in a patient with metastatic Non-Small Cell Lung Cancer (NSCLC)?

Dual IO Therapy Indications in Metastatic NSCLC

Dual immunotherapy with nivolumab plus ipilimumab is indicated for first-line treatment of metastatic NSCLC in patients with PD-L1 ≥1% and no actionable driver mutations, and may be offered to patients with PD-L1 <1% or unknown status, particularly when combined with 2 cycles of platinum-based chemotherapy. 1

Primary Indication: PD-L1 ≥1% Without Driver Mutations

For patients with PD-L1 expression ≥1% and no EGFR/ALK alterations, nivolumab plus ipilimumab represents a category 1 treatment option based on the CheckMate 227 trial demonstrating 5-year OS improvement from 14% to 24% compared to chemotherapy. 1

• In squamous histology with PD-L1 1%-49%, OS increased from 10.6 months to 14.8 months (HR 0.76,95% CI 0.52-1.10), though the study was not powered for subgroup analysis. 1
• The 5-year OS data showed consistent benefit across both squamous and non-squamous histologies (squamous HR 0.63, non-squamous HR 0.55). 1

Alternative Indication: Combination with Chemotherapy (Any PD-L1 Level)

Nivolumab plus ipilimumab combined with 2 cycles of platinum-doublet chemotherapy may be offered to patients regardless of PD-L1 expression or histology. 1

• The CheckMate 9LA trial demonstrated 4-year survival rates of 20% versus 10% in squamous histology, with a 36% reduction in death risk (HR 0.64,95% CI 0.48-0.84). 1
• For PD-L1 1%-49%, the HR for survival was 0.64 (95% CI 0.48-0.84) with median survival 14.5 months versus 9.1 months with chemotherapy alone. 1
• In PD-L1 <1% patients, 4-year OS rates were 23% versus 13% (HR 0.66,95% CI 0.50-0.86). 1
• In non-squamous NSCLC with PD-L1 <1%, the benefit was more modest but statistically significant (4-year OS 22% versus 19%; HR 0.80,95% CI 0.66-0.97). 1

Critical Pre-Treatment Requirements

Before initiating dual IO therapy, you must:

• Confirm absence of EGFR mutations and ALK rearrangements through molecular testing. 1
• Document performance status 0-1 (PS 2 may be considered with caution). 1
• Assess PD-L1 expression level using an FDA-approved assay. 1
• Exclude contraindications to immunotherapy including active autoimmune disease or need for systemic immunosuppression. 1

Specific Clinical Scenarios

Squamous Cell Carcinoma

• For PD-L1 1%-49%: Dual IO with or without chemotherapy is a reasonable option, with the chemotherapy combination showing HR 0.64 (95% CI 0.48-0.84). 1
• For PD-L1 <1%: Dual IO plus 2 cycles chemotherapy may be offered as an alternative to chemoimmunotherapy combinations. 1

Non-Squamous Histology

• For PD-L1 1%-49%: Pembrolizumab plus platinum-pemetrexed remains the preferred standard, but dual IO plus chemotherapy is an acceptable alternative. 1
• For PD-L1 <1%: Dual IO plus chemotherapy may be considered, though the benefit is more modest (HR 0.80). 1

Important Caveats and Safety Considerations

Toxicity profile differs significantly between regimens:

• Dual IO alone: 33% grade ≥3 toxicity, 18% treatment discontinuation due to adverse events. 1
• Dual IO plus chemotherapy: 57% serious adverse events, 2% fatal adverse events. 1
• Grade 3-4 treatment-related adverse events occurred in 14% with dual IO versus 36% with chemotherapy in the neoadjuvant setting. 2

Common pitfalls to avoid:

• Do not use dual IO therapy in patients with EGFR mutations or ALK rearrangements—these patients should receive targeted therapy first-line. 1
• Do not delay molecular testing to start immunotherapy; complete testing before treatment initiation. 1
• Do not use dual IO in patients with PS 3-4; these patients should receive best supportive care only. 1

Regulatory Status

Note that nivolumab plus ipilimumab is not EMA-approved for first-line NSCLC treatment, though it represents an optional treatment regimen in clinical practice guidelines. 1 The combination is FDA-approved in the United States for patients with PD-L1 ≥1%. 1