What is the best treatment approach for a 60-year-old female with adenocarcinoma of the lung, bilateral hilar, mediastinal, and supraclavicular lymph node involvement, and a tumor mutation burden (TMB) of 17?

Treatment for Stage IV Lung Adenocarcinoma with High TMB

For this 60-year-old female with metastatic lung adenocarcinoma (bilateral hilar, mediastinal, and supraclavicular lymph nodes) and TMB of 17 mutations/Mb, nivolumab plus ipilimumab dual immunotherapy is the optimal first-line treatment, regardless of PD-L1 expression status. 1

Critical First Step: Molecular Testing

Before initiating any treatment, you must confirm the absence of actionable driver mutations:

• Test for EGFR mutations (exons 18-21 by sequencing) - if positive, EGFR-TKIs take precedence over immunotherapy 1
• Test for ALK rearrangements (by FISH or IHC) - if positive, ALK inhibitors are preferred over immunotherapy 1
• Test for ROS1, BRAF, RET, and MET alterations - these would change treatment strategy 1
• Testing should focus on non-squamous histology and can be performed in parallel 1

Treatment Algorithm Based on Molecular Results

If Driver Mutation-Negative (Most Likely Scenario)

Primary Recommendation: Dual Immunotherapy

• Nivolumab plus ipilimumab is specifically indicated for patients with TMB ≥10 mutations/Mb, making this patient with TMB 17 an ideal candidate 1
• This regimen works regardless of PD-L1 expression level, eliminating the need to wait for PD-L1 testing 1
• Performance status must be 0-1 for this regimen 1

Alternative Options (in descending order of preference):

1. If PD-L1 TPS ≥50%: Single-agent pembrolizumab 200mg IV every 3 weeks is an acceptable alternative 1

2. If PD-L1 TPS <50% or unknown: Pembrolizumab plus pemetrexed-platinum chemotherapy 1

   • Pembrolizumab 200mg IV + pemetrexed 500mg/m² + carboplatin AUC 5 or cisplatin 75mg/m² every 3 weeks for 4 cycles
   • Followed by pembrolizumab plus pemetrexed maintenance 1

3. If contraindications to immunotherapy exist: Platinum-based doublet chemotherapy 1

   • Pemetrexed is preferred over gemcitabine for non-squamous histology 1
   • Bevacizumab may be added to carboplatin-paclitaxel if no contraindications (no hemoptysis, brain metastases, or anticoagulation) 1

Contraindications to Immunotherapy to Assess

Before proceeding with nivolumab-ipilimumab, exclude:

• Active autoimmune disease requiring systemic immunosuppression 2
• Severe organ dysfunction (performance status >1) 1
• Active infection or immunosuppression 2
• Pregnancy - verify pregnancy status in females of reproductive potential 2

Treatment Duration and Monitoring

• Dual immunotherapy should continue for up to 2 years in the absence of disease progression or intolerable toxicity 1
• Monitor for immune-related adverse events at each visit, particularly pneumonitis, colitis, hepatitis, and endocrinopathies 2
• Patients with severe immunotherapy-related toxicities should discontinue treatment, as this does not impair long-term benefit 1

Critical Pitfalls to Avoid

Do not start immunotherapy without molecular testing - approximately 25% of lung adenocarcinomas harbor EGFR mutations or ALK rearrangements that would make targeted therapy superior to immunotherapy 1

Do not use pembrolizumab monotherapy without confirming PD-L1 ≥50% - the survival benefit is diminished in PD-L1-negative patients 1

Do not overlook performance status - immunotherapy combinations are only recommended for PS 0-1 patients 1

Strongly encourage smoking cessation - continued smoking reduces the bioavailability of targeted therapies and may impact systemic therapy efficacy 1

Staging Confirmation

This patient's presentation (bilateral hilar, mediastinal, and supraclavicular lymph nodes) indicates:

• Stage IV disease (N3, M1a or M1b) based on contralateral mediastinal/hilar and supraclavicular involvement 1
• Complete staging workup required: brain imaging (CT or MRI) and PET-CT to assess for additional metastatic sites 1
• No role for surgical resection in this extensive nodal disease 1

Expected Outcomes

With high TMB (17 mutations/Mb) and dual immunotherapy:

• Higher response rates compared to chemotherapy alone 1
• Durable responses possible even after treatment completion 1
• Potential for long-term survival in responders, though median survival data specific to TMB-high subgroup varies 1