Systemic Therapy

Targeted Therapy

Targeted therapies can be used in a small number of patients with non-small cell lung cancer, often with specific mutations which are the treatment target.

ERBB1 Tyrosine Kinase Inhibitor

Erlotinib is a tyrosine kinase inhibitor that inhibits the function of the ERBB1 transmembrane receptor. It is most effective in patients with activation mutations on exons 19and 21.

  • Patients treated primarily with ERBB1 TKI, when they are shown with these mutations, erlotinib has a significant advantage over cytotoxic chemotherapy in both response rates (60-80%) and progression free survival. Overall survival is not affected, likely due to cross-over protocols employed in modern trial designs.
  • Second line therapy (after progression on systemic cytotoxic therapy), erlotinib was shown to improve outcomes in patients with the activating mutations (BR-21 trial)
  • Maintenance therapy (after response to systemic cytotoxic therapy) with erlotinib has also shown improved progression free and overall survival. Overall survival

Important points:

  • Tests for ERBB1 mutations require sufficient tissue; this is not provided by FNA and patients should have core biopsy or excisional biopsy to acquire sufficient tissue.
  • An additional mutation of ERBB1, known as T790M, causes a structural change in the ERBB1 receptor and prevents binding of erlotinib. This allows signal transduction to occur.
    • This mutation may occur de novo (before exposure to ERBB1 TKI) or develop in response to TKI therapy
    • Second-line tyrosine kinase inhibitors target ERBB1 TKI with the T790M mutation and are in clinical trials
  • Other methods of bypassing ERBB1 TKI effects include increased expression of MET. This membrane bound protein

Side effects:

  • Rash, often acneiform, is the most common (75%)
    • Antibiotics if there is pustule formation (minocycline)
    • Topical steriods can be used
  • Stomatitis/diarrhoea occur in about 20% of patients
  • Rare side effects include paronychia, dry skin and skin exfoliation (<5%)
  • Very rare effects include interstitial lung disease like conditions which can be fatal

ERBB1 Monoclonal Antibody Therapy

Example: Cetuximab

Despite targeting the same receptor as erlotinib, cetuximab shows much poorer results in lung cancer (significant statistically but not clinically). Further analysis has shown that benefit exists in patients with ERBB1 overexpression.

VEGF Monoclonal Antibody Therapy

Example: Bevacizumab

Rationale - Blockage of VEGF receptor prevents stimulation of neoangiogenesis.
ECOG 4599 - Demonstrated a small benefit in progression free survival but no effect on overall survival. Toxicity is increased, particulalry haematological and bleeding.

ALK directed therapy

Example: Crizotinib

ALK mutations are present in 3-5% of non-small cell lung tumours. Crizotinib has been shown in Phase I and II trials to shrink tumour size. Further Phase III studies are pending.