clinical topic updates

Dual Targeting Strategies in Advanced Non–Small Cell Lung Cancer

by Gregory J. Riely, MD, PhD


Early phase studies suggest that dual targeted therapy might have a role in the treatment of advanced non–small cell lung cancer (NSCLC). Dual targeting strategies include those aiming to delay the development of resistance and those aiming to target pathways implicated in resistance that has just emerged.

Expert Commentary

Gregory J. Riely, MD, PhD

Vice Chair, Clinical Research
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY

“We are beginning to think about the use of dual targeting strategies at the time of resistance in patients with EGFR-mutant NSCLC.”

Gregory J. Riely, MD, PhD

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.


Gautschi O, Menon R, Bertrand M, Murer C, Diebold J. Capmatinib and osimertinib combination therapy for EGFR-mutant lung adenocarcinoma. J Thorac Oncol. 2020;15(1):e13-e15. doi:10.1016/j.jtho.2019.07.027

Le X, Nilsson M, Goldman J, et al. Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC. J Thorac Oncol. 2021;16(2):205-215. doi:10.1016/j.jtho.2020.10.006

Nakagawa K, Garon EB, Seto T, et al; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5

Rotow JK, Costa DB, Paweletz CP, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9507. doi:10.1200/JCO.2020.38.15_suppl.9507  

Sequist LV, Han J-Y, Ahn M-J, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet. 2020;21(3):373-386. doi:10.1016/S1470-2045(19)30785-5

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