What is the first-line treatment for advanced non-small cell lung cancer with high PD-L1 expression, specifically using Keytruda (pembrolizumab)?

First-Line Treatment for Advanced NSCLC with High PD-L1 Expression Using Keytruda (Pembrolizumab)

Pembrolizumab monotherapy is the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50% who do not have contraindications to immunotherapy. 1

Treatment Algorithm for Advanced NSCLC with High PD-L1 Expression

For Patients with PD-L1 Expression ≥50%:

1. First choice: Pembrolizumab monotherapy (200mg IV every 3 weeks)

   • Indicated for first-line treatment of metastatic NSCLC expressing PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations 2
   • Strongest evidence supports use in PD-L1 ≥50% population (ESMO-MBCS v1.1 score: 5) 1
   • Associated with doubled median overall survival compared to chemotherapy (30 months vs. 14 months) 1

2. Alternative options when rapid tumor response is needed:

   • For patients with high tumor burden requiring rapid response:
     • Pembrolizumab + pemetrexed + platinum (for non-squamous histology) 1
     • Pembrolizumab + carboplatin + (nab)-paclitaxel (for squamous histology) 1

Key Considerations for Patient Selection:

• Contraindications to immunotherapy must be assessed:

  • Severe autoimmune disease
  • Organ transplantation
  • Active or untreated CNS metastases
  • Poor performance status (PS ≥3)

• Performance status impact:

  • PS 0-1: Optimal candidates for pembrolizumab monotherapy 1
  • PS 2: Consider pembrolizumab monotherapy with caution, as response rates are lower (25.6% vs 43.1%) and median OS significantly shorter (7.4 months vs 20.3 months) compared to PS 0-1 patients 3
  • PS 3-4: Best supportive care recommended 1

Evidence Supporting Pembrolizumab Monotherapy

The phase III KEYNOTE-024 trial established pembrolizumab as superior to platinum-based chemotherapy in patients with PD-L1 ≥50%, demonstrating:

• Improved overall survival (HR 0.6)
• Improved progression-free survival (HR 0.5)
• Higher objective response rate (45% vs 28%)
• Better safety profile and quality of life 1

Long-term follow-up data from KEYNOTE-001 showed that patients with PD-L1 TPS ≥50% had:

• Higher objective response rate (51.9%)
• Better 12-month progression-free survival (54%)
• Better 12-month overall survival (85%) compared to the overall population 4

Pembrolizumab Monotherapy vs. Pembrolizumab-Chemotherapy Combination

While pembrolizumab monotherapy is the standard for PD-L1 ≥50% patients, adding chemotherapy may provide additional benefits in specific scenarios:

• Indirect comparisons suggest pembrolizumab plus chemotherapy may be superior to pembrolizumab alone in terms of:
  • Objective response rate (RR 1.62)
  • Progression-free survival (HR 0.55) 5
• Consider combination therapy for patients with:
  • Symptomatic disease requiring rapid response
  • High tumor burden
  • Brain metastases (if controlled)

Treatment Duration and Follow-up

• Pembrolizumab treatment may be continued for up to 35 cycles (approximately 2 years) 1
• Treatment should be adjusted based on clinical efficacy and tolerability 1
• Immunotherapy can be discontinued after 2 years in most cases 1

Management After Progression

For patients progressing on first-line pembrolizumab:

• Platinum-based chemotherapy is recommended as second-line treatment 1
• Options include:
  • For non-squamous histology: Platinum + pemetrexed
  • For squamous histology: Platinum + gemcitabine/taxane

Pitfalls and Caveats

1. Ensure proper PD-L1 testing using an FDA-approved assay before initiating therapy
2. Rule out EGFR mutations and ALK rearrangements before starting pembrolizumab
3. Monitor for immune-related adverse events which can affect any organ system
4. Be aware that hyperprogression can occur in a small subset of patients
5. Pseudoprogression may occur; continue treatment if clinically stable despite radiographic progression
6. Poor performance status patients (PS 2) have significantly worse outcomes with immunotherapy compared to PS 0-1 patients

By following this algorithm, clinicians can optimize the use of pembrolizumab for patients with advanced NSCLC and high PD-L1 expression, potentially achieving durable responses and improved survival outcomes.