What is the second-line treatment for non-small cell lung cancer (NSCLC) that progresses after first-line treatment?

Second-Line Treatment for Progressive NSCLC

For patients with NSCLC that progresses after first-line therapy, PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab) are the treatment of choice for most patients with PS 0-2, regardless of PD-L1 expression, unless they received immunotherapy in first-line treatment. 1

Treatment Algorithm Based on First-Line Therapy

After First-Line Immunotherapy

• For patients who progressed after first-line immunotherapy with pembrolizumab, platinum-based chemotherapy is recommended as second-line treatment 1

After First-Line Chemotherapy (PD-L1 inhibitor-naive)

• PD-L1 and PD-1 inhibitors are preferred:
  • Nivolumab for both squamous and non-squamous NSCLC 1
  • Pembrolizumab for patients with PD-L1 expression >1% 1
  • Atezolizumab for patients previously treated with one or two prior lines of chemotherapy 1

For Patients Not Suitable for Immunotherapy

• Single-agent chemotherapy is recommended:
  • Pemetrexed for non-squamous histology only 1
  • Docetaxel for all histologies (with more favorable tolerability profile for pemetrexed in non-squamous) 1
  • Treatment may be prolonged if disease is controlled and toxicity is acceptable 1

Additional Options Based on Histology

For Adenocarcinoma

• Nintedanib/docetaxel combination, especially in patients progressing within 9 months from the start of first-line chemotherapy 1

For All Histologies

• Ramucirumab/docetaxel is a treatment option in patients progressing after first-line chemotherapy 1, 2
• Erlotinib represents a potential second/third-line option particularly for patients not suitable for immunotherapy or chemotherapy with unknown EGFR status or EGFR wild-type tumors 1

For Patients with Oncogenic Drivers

• Any patient with a tumor bearing an activating EGFR mutation should receive an EGFR TKI if not received previously 1
• Patients with ALK fusion should receive crizotinib if not received previously 1

Patient Selection Considerations

• Patients with PS 0-2 should be offered second-line therapy 1
• Response to first-line therapy and performance status are strong predictors of benefit from second-line treatment 3, 4
• Age alone should not determine selection of second-line therapy 1

Common Pitfalls and Caveats

• PD-L1 testing should be performed at diagnosis to guide treatment decisions for both first and second-line therapy 1
• Treatment beyond second-line should be considered for selected patients with good performance status who had disease control with previous lines of therapy 4, 5
• The evidence suggests that patients with good performance status after progression from third-line therapy could benefit from fourth-line therapy 5
• Treatment duration should be individualized based on disease control and toxicity 1

Special Considerations

• For squamous cell carcinoma with PS 0-2 unfit for chemotherapy or immunotherapy, afatinib is a potential option 1
• Histology is an important factor in treatment selection, particularly for pemetrexed which is only effective in non-squamous histology 1, 6
• Patients who have radiological progression with ongoing clinical benefit from targeted therapies may continue treatment with the addition of local therapy to progressing sites 1