Weighing Options for First-Line Therapy in EGFR-Mutated NSCLC

The selection of a first-line treatment for patients with advanced EGFR-positive non-small cell lung cancer (NSCLC) has become increasingly complex in recent years with available options now including osimertinib (Tagrisso, as monotherapy or with chemotherapy) and amivantamab (Cyramza) plus lazertinib (Lazcluze).

During a session at the 2025 American Society of Clinical Oncology (ASCO) meeting, several NSCLC specialists debated dilemmas associated with the selection of front-line therapy in this patient population.

“Incorporating disease characteristics, patients’ goals and values, and an individual’s preference for the balance of efficacy and toxicity is critical to making the best shared decision,” said the session chair Jessica Bauman, MD, of Fox Chase Cancer Center in Philadelphia.

Any therapy chosen ideally would have a high efficacy and high convenience with a low toxicity and cost, but reality often doesn’t reach that goal, Bauman said.

Walking through each of the currently available options, Bauman characterized osimertinib as having moderate-to-high efficacy, with low toxicity, relatively low cost, and high convenience. The addition of chemotherapy increases efficacy but also toxicity and cost, and makes the regimen less convenient. Finally, amivantamab and lazertinib have higher efficacy in terms of both progression-free and overall survival, but also higher toxicity and cost, with less convenience.

Bauman was joined by Julia Rotow, MD, of the Dana-Farber Cancer Institute in Boston, and Alessio Cortellini, MD, PhD, of Campus Bio-Medico University of Rome, in debating the use of an osimertinib monotherapy approach compared with the use of combination therapy.

Monotherapy a Good Option

Rotow acknowledged that the use of combination osimertinib and chemotherapy does improve progression-free survival (PFS) and can improve overall survival (OS) in patients with newly diagnosed, EGFR-mutated NSCLC. This is supported by data from the FLAURA2 trial that showed that osimertinib plus a platinum doublet improved median PFS compared with osimertinib alone (25.5 vs 16.7 months), and with data from MARIPOSA that showed amivantamab plus lazertinib improved both PFS (23.7 vs 16.6 months) and OS (not reached vs 36.7 months) compared with osimertinib alone.

“For many of our patients, an upfront combination can be our new [standard of care] with newly diagnosed, EGFR-mutated lung cancer,” said Rotow. However, she questioned how many real-world patients stand to benefit.

“In practice, we know that even one comorbid medical condition substantially decreases the probability of clinical trial discussion, trial offer, and trial participation,” Rotow said. For example, data showed that 55% of patients treated with first-line osimertinib at Beth Israel Deaconess Medical Center in Boston would not have met eligibility for the FLAURA trial; and being trial eligible was associated with significantly longer time to treatment discontinuation and OS.

Another question raised by Rotow: “Are there patients deriving less benefit from upfront combination therapy because of lower risk features where the downsides may outweigh the gains?”

Certain features do, in fact, predict better PFS with osimertinib, she said, such as EGFR exon 19 deletion mutations, lack of TP53 and RB1 co-mutation, and early plasma clearance of the EGFR mutation. This is borne out in monotherapy and combination therapy trials, Rotow said.

Combos for All

In contrast, Cortellini — with the disclaimer that he was assigned to argue in favor of combination therapy — said that first-line combinations should be used in all patients with EGFR-mutated NSCLC “to avoid losing patients across treatment lines.”

The aggressive nature of lung cancer supports the use of the best therapies earlier in treatment, he said. Historical data looking at first-, second-, and third-generation TKIs show that, even in the controlled environments of clinical trials, 12-40% of patients were lost in the second-line setting. Data from MARIPOSA and FLAURA2 support this trend, he said. For example, in MARIPOSA, about 25% of patients who discontinued and progressed did not receive a second-line treatment.

“The message here is that if we choose not to use a combo upfront, we risk denying 1 out of 3 or 4 of our patients to receive the most active treatment, with the potential implication for OS,” Cortellini said.

Indeed, there is clinical benefit for combination strategies across high-risk subgroups, such as those with CNS metastases, TP53 co-mutations, and those with detectable circulating tumor DNA. In contrast, outcomes with osimertinib monotherapy in these groups is suboptimal.

What About Toxicity?

Rotow emphasized that the efficacy outcomes of these regimens could not be discussed without talking about toxicity, patient preference, and quality of life.

“We know the frequency and grade of toxicities are higher with combination therapy upfront,” Rotow said. Looking at data from MARIPOSA, she said, “there is quite a lot more grade 2, grade 3, cutaneous toxicity, MET-related toxicity, and infusion related reactions, and these all impact patient quality of life in an ongoing fashion through potential years of therapy.”

She also pointed out that the FLAURA2 regimen is often discussed as a “better tolerated regimen,” but it still involves upfront chemotherapy with a higher rate of all-grade and grade 3 toxicity when chemotherapy is added to osimertinib.

Looking at patient clinic visits, Rotow estimated about seven visits with osimertinib monotherapy, about 19 visits with osimertinib plus chemotherapy, and about 30 visits with amivantamab and lazertinib, all assuming there are no extra encounters for side effect management.

“While many patients with newly diagnosed EGFR-mutated NSCLC will have improved survival outcomes with first-line combination therapy regimens, this strategy comes at the cost of increased toxicities and adverse impact on quality of life,” Rotow said. “Therefore, when considering and making recommendations about frontline therapy, we need to assess for both disease-based risk characteristic and patient preference to give our best recommendation.”

Commenting on the toxicity, Cortellini said that toxicity with the MARIPOSA regimen appears to be front loaded but declines over time. In fact, there are data suggested that toxicity tends to decline after month 4, but Cortellini pointed out that this is likely because of dose interruptions as a result of “fine tuning.”

“Fortunately, we also have data showing that early dose interruptions do not affect clinical outcomes,” he said.

When faced with the decision of selecting a front-line therapy, Bauman also reviewed data on early integration of supportive and palliative care both to balance efficacy and toxicity and to help patients with symptom management and complex decision-making.