What is the treatment regimen for a patient with advanced lung cancer using Nivolumab (nivolumab) and Ipilimumab (ipilimumab), considering tumor mutational burden and prior treatments?

Nivolumab Plus Ipilimumab for Advanced Lung Cancer

Nivolumab plus ipilimumab is a first-line treatment option specifically for patients with advanced NSCLC who have high tumor mutational burden (TMB ≥10 mutations/megabase), regardless of PD-L1 expression level, with performance status 0-1 and no EGFR/ALK mutations. 1

Patient Selection Criteria

High TMB is the critical biomarker for this combination:

• TMB ≥10 mutations/megabase identifies patients who benefit from nivolumab plus ipilimumab over chemotherapy 1, 2
• This regimen works regardless of PD-L1 expression level—patients with PD-L1 <1% and ≥1% both benefit when TMB is high 1, 2
• Both squamous and non-squamous histologies respond (HR 0.63 for squamous, HR 0.55 for non-squamous) 1

Absolute requirements:

• Performance status 0-1 1
• EGFR and ALK negative disease 1
• No contraindications to immunotherapy 1

Treatment Regimen

The FDA-approved dosing schedule is: 3

• Nivolumab 3 mg/kg every 3 weeks PLUS ipilimumab 1 mg/kg every 3 weeks
• Administer both as 30-minute IV infusions on the same day
• Continue combination for maximum 4 doses or until unacceptable toxicity
• After completing 4 combination doses, continue nivolumab monotherapy (240 mg every 2 weeks or 360 mg every 3 weeks) until disease progression, unacceptable toxicity, or up to 2 years 3

Alternative dosing for metastatic NSCLC with PD-L1 ≥1%: 3

• Nivolumab 360 mg every 3 weeks PLUS ipilimumab 1 mg/kg every 6 weeks
• Continue until disease progression, unacceptable toxicity, or up to 2 years

Efficacy Data

In patients with high TMB (≥10 mut/Mb), the combination demonstrates superior outcomes: 2

• Median progression-free survival: 7.2 months versus 5.5 months with chemotherapy (HR 0.58)
• 1-year PFS rate: 42.6% versus 13.2% with chemotherapy
• Objective response rate: 45.3% versus 26.9% with chemotherapy
• Response rate remains high (47-48%) even in PD-L1 <1% patients when TMB is high 4

Long-term survival benefits are substantial: 5

• Median overall survival: 18.6 months in pooled analysis
• 3-year OS rate: 35% overall
• Median duration of response: 23.7 months
• 38% of responders maintain response at 3 years

Depth of response correlates with survival: 5

• Tumor burden reduction ≥80%: 3-year OS rate 85%
• Tumor burden reduction 50-<80%: 3-year OS rate 72%
• Tumor burden reduction 30-<50%: 3-year OS rate 44%

When NOT to Use This Regimen

This combination is NOT appropriate for:

• Patients with TMB <10 mutations/megabase—use alternative immunotherapy strategies (pembrolizumab monotherapy if PD-L1 ≥50%, or pembrolizumab plus chemotherapy) 1
• EGFR-mutated or ALK-rearranged NSCLC—targeted therapy is first-line 1
• Active autoimmune disease requiring systemic immunosuppression 6
• Performance status ≥2 1

Safety Profile and Management

Grade 3-4 treatment-related adverse events occur in 31% of patients, which is actually lower than chemotherapy (36%): 2

Common immune-related adverse events requiring monitoring: 3

• Colitis: Grade 2—withhold both agents; Grade 3-4—permanently discontinue
• Hepatitis: If AST/ALT >3-5× ULN or bilirubin >1.5-3× ULN—withhold; if higher—permanently discontinue
• Pneumonitis: Grade 2—withhold; Grade 3-4—permanently discontinue
• Endocrinopathies: Can continue with hormone replacement for Grade 2

Critical management principle: When administering combination therapy, withhold or permanently discontinue BOTH nivolumab and ipilimumab together for toxicity 3

Common Pitfalls to Avoid

Do not use this regimen without TMB testing—the benefit is specifically in high TMB patients, and lower TMB patients have better alternatives 1, 2

Do not continue ipilimumab beyond 4 doses—the regimen is designed as 4 cycles of combination followed by nivolumab maintenance 3

Do not assume PD-L1 expression predicts benefit with this combination—TMB is the relevant biomarker here, not PD-L1 1, 2

Do not use in maintenance setting after chemotherapy—CheckMate 451 showed no OS benefit for nivolumab plus ipilimumab as maintenance therapy in extensive-stage SCLC (HR 0.92, P=0.37) 7