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Experts Debate Addition of Frontline Chemotherapy for EGFR+ NSCLC

*March 2024*

The publishing of data from the FLAURA21 and MARIPOSA2 trials in the fall of 2023 spurred much discussion and debate about the use of first-line chemotherapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations.

To clarify the role of first-line chemotherapy in this population, Suresh S. Ramalingam, MD, and Joshua K. Sabari, MD, debated the pros and cons during the 2024 Targeted Therapies of Lung Cancer meeting, which took place February 21-24 in Santa Monica, California.

Dr. Ramalingam, Executive Director of Winship Cancer Institute of Emory University, Atlanta, argued first-line therapy for all EGFR patients should be chemotherapy plus a TKI. He said there are three key points to consider when reviewing the evidence: improved progression-free survival (PFS), central nervous system (CNS) activity, and good tolerability.

“Let’s look at how osimertinib became first-line therapy in the first place,” he said. “Compared to previous generations of treatments, there was improvement in PFS, improvement in CNS activity, and good tolerance. I would say the answer is very clear that chemo plus osimertinib should be standard of care [for the same reasons].”

Dr. Ramalingam supported his position by reviewing data from FLAURA2, which showed a 10-month improvement in median PFS when patients received chemotherapy plus osimertinib compared to osimertinib alone. Additionally, patients with brain metastasis also had about a 10-month improvement in median PFS,

“The other point to keep in mind is when patients get first-line osimertinib—these are data from the FLAURA study—only about 65% of the patients went on to receive a subsequent therapy after first-line osimertinib. There’s a one out of three chance that your first-line therapy is the last therapy that the patient will see. So you want to maximize the ability to achieve durable disease control, and that’s another reason to think about using chemo plus osimertinib in the frontline setting.”

Joshua K. Sabari, MD
Joshua K. Sabari, MD

Dr. Ramalingam also addressed the heterogeneity of EGFR-mutated lung cancers.

“Reports show that EGFR-mutated lung cancers are not a monolithic entity,” he said. “There’s clonal heterogeneity. There are co-mutations. Therefore, single agent therapy may not be able to achieve what combination therapy can achieve… We also know that when you give chemo plus osimertinib, you stand a better chance of avoiding the development or emergence of drug-tolerant persister cells. So that’s yet another reason why chemo plus osimertinib in this patient population may be beneficial.”

However, Dr. Sabari, Assistant Professor in the Department of Medicine at New York University Grossman School of Medicine, New York, said first-line TKI monotherapy remains the preferred therapy for many EGFR-positive patients.

First, Dr. Sabari said the overall survival (OS) data from FLAURA2 and MARIPOSA remains immature (Fig. 1). Read more.