Elaine Shum, MD is an Assistant Professor of Medicine at NYU Perlmutter Cancer Center in New York.

Dr Shum on Evolving First-Line Treatment Approaches for EGFR-Mutant NSCLC

“Thankfully, there are so many first-line options now for patients with stage IV 

-mutated lung cancers. Honestly, we still aren’t sure exactly what the best regimens we should be referring patients to are. There are a lot of data coming out every day that sometimes skew what we do one day to the next, but the most important thing so far is certainly about efficacy.”

Elaine Shum, MD, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, as well as director of Cancer Screening Programs at NYU Langone Health, discussed clinical decision-making factors regarding first-line therapy for patients with 

-mutant non–small cell lung cancer (NSCLC).

The optimal first-line treatment strategy for patients with stage IV 

-mutated NSCLC remains an evolving area of investigation, Shum began. Fortunately, the therapeutic paradigm has significantly expanded over recent years, offering multiple treatment options, she said. However, there remains uncertainty regarding the most effective regimen to recommend, and emerging data influence clinical decision-making on an ongoing basis, she noted.

At present, therapeutic efficacy remains a primary consideration. The oncology community is anticipating the full overall survival data readout from the phase 3 FLAURA2 trial (NCT04035486) of osimertinib (Tagrisso) with or without chemotherapy, which are expected to further inform treatment strategies, according to Shum. Relevant data from the phase 3 MARIPOSA trial (NCT04487080) of amivantamab-vmjw (Rybrevant) plus lazertinib (Lacluze) vs osimertinib have previously been reported, and outcomes from the phase 3 FLAURA trial (NCT02296125) evaluating osimertinib monotherapy have also helped frame treatment decision-making, she explained. Nevertheless, these regimens have not been compared in head-to-head clinical trials, she cautioned. As such, selection between these treatment options requires careful patient-provider discussions, particularly regarding differences in toxicity profiles, anticipated adverse effects, and logistical considerations like treatment administration schedules and monitoring burden, Shum stated. These factors are critical in shaping treatment recommendations, especially when considering monotherapy vs combination regimens, she emphasized.

Additionally, certain high-risk clinical and molecular features may influence the selection of more intensive therapeutic approaches, Shum reported. For instance, the presence of brain metastases at diagnosis, or co-occurring genomic alterations like 

 mutations, may be indicative of a more aggressive disease phenotype, she continued. These factors are integrated into the clinical decision-making process when evaluating the appropriateness of combination therapies, Shum concluded.

Videos

Elaine Shum, MD, discusses questions that remain regarding the first-line treatment paradigm for patients with EGFR-mutant non–small cell lung cancer.

Dr Shum on the Evolving Treatment Paradigm for EGFR+ NSCLC

"In 2025, we are certainly seeing [a shift], especially in the first-line setting for treatment of 

-mutated lung cancer, where combination treatments or regimens have definitely entered our paradigm—marking a significant change from how it used to be with just single-agent EGFR inhibitors."

Elaine Shum, MD, a thoracic medical oncologist at NYU Langone’s Perlmutter Cancer Center, discussed the shifting treatment paradigm in 

-mutated non–small cell lung cancer (NSCLC), emphasizing the growing role of combination regimens in the frontline setting and the implications of recent phase 3 trial data.

Historically, first-line treatment for patients with 

-mutated NSCLC has centered on single-agent EGFR TKIs, with osimertinib (Tagrisso) representing the standard of care in this patient population based on its intracranial activity and survival benefits. However, Shum noted that the field has reached a turning point with increasing clinical evidence supporting the integration of combination strategies aimed at delaying resistance and improving long-term outcomes.

Two key studies driving this evolution were the phase 3 FLAURA2 (NCT04035486) and the MARIPOSA (NCT04487080) trials. In FLAURA2, the addition of platinum-based chemotherapy to osimertinib was evaluated in the frontline setting, with data showing a clinically meaningful improvement in progression-free survival compared with osimertinib alone. This approach sought to broaden therapeutic impact by addressing both 

-dependent and -independent disease mechanisms.

MARIPOSA investigated the combination of amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze), in treatment-naive patients. This regimen was compared against osimertinib monotherapy and lazertinib monotherapy, and findings from the study 

The trials have highlighted the trend toward redefining first-line standards for 

-mutant NSCLC, with combination approaches increasingly favored in select patient populations. Shum noted that these strategies may be particularly beneficial for patients at higher risk of early progression, though optimal patient selection remains an area of ongoing investigation.

Although osimertinib monotherapy continues to offer a favorable safety profile and remains a key therapeutic option, the addition of chemotherapy or targeted biologics reflects a nuanced shift in treatment strategy. Shum emphasized that as more data mature, the field must continue to refine first-line approaches based on clinical risk factors, molecular profiles, and emerging resistance patterns.

Elaine Shum, MD, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, discusses emerging targeted therapies in 

A growing area of research is aimed at understanding resistance mechanisms that develop following progression on osimertinib (Tagrisso) in patients with 

-mutant NSCLC, explains Shum. Although these efforts are largely ongoing, the field hopes to establish a standard of care for patients.

For example, trials are under way evaluating various combinations of MET inhibitors plus osimertinib to try to overcome these resistance mechanisms, Shum says. 

Additionally, the investigational agent JNJ-6372 is being evaluated in patients with metastatic NSCLC who harbor 

 exon 20 insertion mutations, continues Shum. 

Other research efforts seek to understand why patients may develop 

 amplifications and C797S resistance mutations after osimertinib, Shum concludes. 

Elaine Shum, MD, discusses emerging targeted therapies in EGFR-mutant non–small cell lung cancer.  



Dr. Shum on Emerging Targeted Therapies in EGFR-Mutant NSCLC 

Elaine Shum, MD, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, discusses consulting patients with non–small cell lung cancer (NSCLC) on the use of osimertinib (Tagrisso).

The primary end point of the phase 3 ADAURA trial was looking at patients with stage II and III NSCLC, as well as those with stage IB disease, says Shum. An impressive hazard ratio for disease-free survival of 0.17 was observed in that group of patients, says Shum. This trial should be discussed with patients who have had resected lung cancer with an 

 mutation, according to Shum. For patients with stage II or III disease, it's definitely an option that can be pursued, says Shum.

For those with stage IB lung cancer, adjuvant chemotherapy is an option, although there is no set standard as to who receives it and who does not. In the clinic, having a discussion with the patient about whether or not to use osimertinib for 3 years for stage IB resected NSCLC is needed, concludes Shum.

Elaine Shum, MD, discusses consulting patients with non-small cell lung cancer on the use of osimertinib.

Dr. Shum on Patient Consultation of Osimertinib in NSCLC

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses the use of dacomitinib (Vizimpro) in the treatment of patients with 

-positive non—small cell lung cancer (NSCLC).

The second-generation EGFR TKI had very impressive data in the ARCHER 1050 study, Shum says, but the toxicity profile of the drug may be reason for concern. With dacomitinib, there is much stronger toxicity than what is typically observed with this class of drugs, especially when compared with osimertinib (Tagrisso), the frontline standard of care. Shum notes that personally, she would not consider using dacomitinib in the frontline due to toxicity alone. However, as more is understood about sequencing EGFR TKIs, dacomitinib could have a potential role in later lines of therapy.

In September 2018, the FDA approved dacomitinib as a frontline treatment option for patients with metastatic NSCLC who harbor 

 exon 19 deletion or exon 21 L858R substitution mutations. The approval was based on positive data from the phase III ARCHER 1050 trial, which showed a 40% reduction in the risk of disease progression or death compared with the first-generation EGFR TKI gefitinib (Iressa).

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses the use of dacomitinib in the treatment of patients with EGFR-positive non–small cell lung cancer.

Dr. Shum Discusses Dacomitinib in EGFR+ NSCLC

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses mechanisms of resistance in patients with oncogene-driven non—small cell lung cancer (NSCLC).

Based on data from the phase III FLAURA and ALEX studies, osimertinib (Tagrisso) and alectinib (Alecensa) have become the recommended frontline treatments for patients with 

-positive NSCLC, respectively. Physicians are still learning why tumors develop mechanisms of resistance, says Shum. Although there is no substantial insight into why this occurs, there is reason to believe that these targeted agents isolate a clone and allow for another clone to drive the disease undetected. Future studies involving more biopsies at the time of progression will hopefully shed more light on this issue, she adds.

For patients who have developed resistance to treatment, combination therapy with various TKIs may be a potential strategy, says Shum, although toxicity may become an issue. Additionally, some anecdotal studies have shown improved outcomes with an EGFR inhibitor and MET inhibitor in 

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses mechanisms of resistance in patients with oncogene-driven non–small cell lung cancer (NSCLC).

Elaine Shum, MD

Articles

Dr Shum on Evolving First-Line Treatment Approaches for EGFR-Mutant NSCLC

Dr Shum on the Evolving Treatment Paradigm for EGFR+ NSCLC

Dr. Shum on Emerging Targeted Therapies in EGFR-Mutant NSCLC

Dr. Shum on Patient Consultation of Osimertinib in NSCLC

Dr. Shum Discusses Dacomitinib in EGFR+ NSCLC

Dr. Shum on Mechanisms of Resistance in Oncogene-Driven NSCLC