The treatment of cancer has always involved combinations. Whether it is platinum-based combination chemotherapy for patients with NSCLC or the multidrug regimens for hematologic malignancies, targeting more than 1 pathway can often lead to better outcomes for our patients. Recently, the use of dual targeted therapy has been evaluated as initial treatment for patients with EGFR-mutant NSCLC. Dual targeting is also being explored in the treatment of EGFR-mutant NSCLC that has developed resistance to initial monotherapy.

In the frontline EGFR-mutant NSCLC setting, we have seen data suggesting that the addition of a VEGF-targeting agent such as bevacizumab or ramucirumab results in improved progression-free survival compared with EGFR tyrosine kinase inhibitor (TKI) therapy alone. The combination of erlotinib plus ramucirumab was associated with significantly improved progression-free survival compared with erlotinib alone; this combination was approved by the US Food and Drug Administration for NSCLC in 2020. We also have similar data with erlotinib plus bevacizumab, although the data are not quite as consistent. Finally, there are ongoing studies evaluating newer EGFR TKIs such as osimertinib in combination with VEGF-targeting agents (ie, ramucirumab or bevacizumab).

Mechanisms of resistance for EGFR-mutant NSCLC are also being investigated to potentially identify drug combinations that can be used to prevent resistance. This has led to the evaluation of the concurrent use of 2 different EGFR TKIs. A phase 1/2 study presented at the 2020 American Society of Clinical Oncology Annual Meeting described the use of osimertinib plus gefitinib for the first-line treatment of patients with EGFR-mutant NSCLC. The results demonstrated the ability to coadminister those drugs, although the results are very preliminary; it is not yet known whether it is better to start with 2 different EGFR TKIs or to use 1 and then switch when resistance emerges.

We are beginning to think about the use of dual targeting strategies at the time of resistance in patients with EGFR-mutant NSCLC. The best example of this is the use of EGFR TKIs plus MET inhibitors at the time of resistance in those with EGFR-mutant NSCLC who become resistant to an EGFR TKI and then develop MET amplification. Using a variety of MET inhibitors and a variety of EGFR TKIs, we have seen reasonable clinical efficacy for some of these combinations. This approach is certainly worthy of further study.