Erlotinib is a small molecule inhibitor of the tyrosine kinase domain associated with the EGFR. It is now approved as first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations and are refractory to at least one prior chemotherapy regimen. It is also approved for maintenance therapy of patients with metastatic NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. Patients who are nonsmokers and who have a bronchoalveolar histologic subtype appear to be more responsive to these agents. In addition, erlotinib has been approved for use in combination with gemcitabine for the treatment of advanced pancreatic cancer. It is metabolized in the liver by the CYP3A4 enzyme system, and elimination is mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that also are metabolized by the liver CYP3A4 system, such as phenytoin and warfarin, and the use of grapefruit products should be avoided. An acneiform skin rash, diarrhea, and anorexia and fatigue are the most common adverse effects observed with these small molecules (Table 54–5).
Afatinib is a small molecule inhibitor of the tyrosine kinase domains associated with EGFR, HER2 and HER4, and causes inhibition of downstream ErbB signaling. It is approved for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations. The toxicities associated with this agent are similar to those seen with erlotinib.
Osimertinib is a small molecule inhibitor approved in 2015 for the treatment of metastatic EGFR T790M mutant NSCLC following progression on or after EGFR tyrosine kinase inhibitor therapy. In addition to targeting the T790M mutant, this agent targets the L858R and exon 19 EGFR mutations. The adverse effect profile is similar to erlotinib and afatinib, but unique cardiac toxicities are associated with this agent, including QTc prolongation and cardiomyopathy.
Bevacizumab, Ziv-Aflibercept, Ramucirumab, Sorafenib, Sunitinib, & Pazopanib
Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors. The growth of both primary and metastatic solid tumors requires an intact vasculature; thus the VEGF signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEGF signaling; they include inhibition of VEGF interactions with its receptor by targeting either the VEGF ligand with antibodies or soluble chimeric decoy receptors, or by direct inhibition of VEGF receptor–associated tyrosine kinase activity by small molecule inhibitors.