Updated OS Data Reshape First- and Second-Line Treatment Selection in EGFR-Mutated Advanced NSCLC

December 22, 2025 | Courtney Flaherty

Updated overall survival (OS) findings from the phase 3 FLAURA2 trial (NCT04035486), together with prior data from the phase 3 MARIPOSA (NCT04487080) and MARIPOSA-2 (NCT04988295) trials, have sharpened ongoing debate around treatment intensification vs de-escalation in EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to panelists participating in an OncLive^® Scientific Interchange and Workshop.¹

During the workshop, which was held during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer (2025 WCLC), panelists unpacked topline data from FLAURA2, MARIPOSA, MARIPOSA-2, and related studies, and discussed how these findings are informing real-world selection between single-agent osimertinib (Tagrisso) and osimertinib- or amivantamab (Rybrevant)–based combination regimens in the frontline setting.

“The goal of [this discussion was not only] to evaluate current and emerging therapeutic strategies and compare the improved efficacy outcomes with combination therapy, but also to weigh increased toxicity and identify best practice sequencing strategies for first-line and subsequent treatment based on available data,” Helena Yu, MD, moderator of the workshop and a thoracic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, stated.

What do data suggest about the benefit of osimertinib with or without chemotherapy?

In February 2024, the FDA approved osimertinib in combination with platinum-based chemotherapy for patients with locally advanced or metastatic EGFR-mutated NSCLC harboring exon 19 deletions or exon 21 L858R substitutions, as detected by an FDA-approved test.2 This decision was supported by findings from FLAURA2.

Final OS data from FLAURA2 presented during the 2025 WCLC showed that, at a median follow-up of 51.2 months (range, 0.2-60.4) in the osimertinib plus chemotherapy arm (n = 279) and 51.3 months (range, 0.1-60.1) in the osimertinib monotherapy arm (n = 278), the median OS was 47.5 months (95% CI, 41.0-not calculable) with the combination vs 37.6 months (95% CI, 33.2-43.2) with monotherapy (HR, 0.77; 95% CI, 0.61-0.96; P = .02).3 The 3-year OS rates were 63% and 51%, respectively, and the 4-year OS rates were 49% and 41%, respectively.

Panelists noted that the OS HR was more favorable than anticipated and that the survival curves had not converged to the extent expected with longer follow-up, and remarked that the magnitude of progression-free survival (PFS) benefit observed in patients with brain metastases was unexpected. Questions were raised regarding the biological mechanism underlying these findings and whether early chemotherapy meaningfully alters post-progression outcomes.

“The HR [for OS] in FLAURA2 was better than I thought,” Jeffrey P. Ward, MD, PhD, an assistant professor of medicine in the Division of Oncology, the Department of Medicine, at Washington University School of Medicine in St Louis, Missouri, noted. “The crossover rate was pretty high, but I thought [the curve] was going to narrow more, given the amount of chemotherapy patients received later. This raises many mechanistic scientific questions about what is occurring early on.”

“The shape of these curves leads one to consider what is being accomplished by adding chemotherapy upfront,” Jared Weiss, MD, section chief of Thoracic and Head/Neck Oncology and a professor of medicine-oncology at UNC School of Medicine in Chapel Hill, North Carolina, weighed in.

What data support amivantamab plus lazertinib as a frontline treatment alternative?

The combination of amivantamab plus lazertinib (Lazcluze) serves as an alternative to frontline osimertinib plus chemotherapy for the treatment of patients with EGFR-mutated NSCLC. In August 2024, this regimen received FDA approval for untreated locally advanced or metastatic EGFR-mutated NSCLC based on findings from MARIPOSA.4

Updated data from MARIPOSA, published in The New England Journal of Medicine and discussed at the 2025 WCLC, showed a significant OS benefit with amivantamab plus lazertinib vs osimertinib.5 At a median follow-up of 37.8 months (range, 0.0-48.1), median OS was not estimable (NE; 95% CI, 42.9 months-NE) with amivantamab plus lazertinib vs 36.7 months (95% CI, 33.4-41.0) with osimertinib (HR, 0.75; 95% CI, 0.61-0.92; P = .005).

However, panelists stated that the lack of crossover in MARIPOSA represented a major limitation in interpreting the OS benefit, and questioned whether the observed survival advantage could be definitively attributed to the experimental regimen.

“My interpretation of these curves is that we do not know what survival advantage amivantamab plus lazertinib offers over osimertinib in the current environment [without planned crossover],” Ward stated.

“Some patients will have more of an immune response because the mechanism of action [of amivantamab] involves trogocytosis and phagocytosis. That is where [the data in] this study differ from the FLAURA2 curves,” Eric K. Singhi, MD, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology and the Department of General Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, noted. “The [lack of] crossover is an important point. Some patients will have a prolonged or even an amivantamab-free response. I don’t know if every patient needs to receive thrice-weekly amivantamab in perpetuity.”

Panelists also stated that mandated brain magnetic resonance imaging in MARIPOSA resulted in higher-quality central nervous system data, which was viewed as a strength of the trial.

What patient factors and toxicities should be weighed during frontline treatment selection?

Panelists emphasized that treatment selection in the frontline setting must remain individualized. Although treatment intensification has been a prevailing goal in recent years, there is increasing interest in identifying patients for whom de-escalation to monotherapy is appropriate, particularly when quality of life and patient preferences are prioritized through shared decision-making. Disease characteristics such as the presence of asymptomatic metastatic disease and intracranial involvement were also noted to influence decision-making.

“Two years ago, we were searching for reasons to intensify treatment for patients. Now, it’s almost the opposite; I’m searching for reasons not to intensify and to de-escalate to single-agent osimertinib,” Singhi shared. “The treatment of these patients is based not so much on age, but on their performance status, goals, and quality of life. Thinking through the toxicities and discussing them with patients to see if they are willing to sign up for these regimens is essential.”

The panelists acknowledged that many patients are both “toxicity-averse and chemotherapy-averse”; even when combination therapy is recommended, patients often choose osimertinib monotherapy. However, panelists agreed that the majority of patients are now receiving osimertinib plus chemotherapy. When comparing osimertinib plus chemotherapy with amivantamab plus lazertinib, panelists reported greater real-world use of the former.

“I’d say 25% to 30% of my patients receive single-agent osimertinib even now, while another 65% to 70% receive chemotherapy plus osimertinib,” Kaushal Parikh, MBBS, a medical oncologist and assistant professor of oncology at Mayo Clinic in Rochester, Minnesota, reported. “First, patients understand that this is just 4 cycles of chemotherapy followed by maintenance, as opposed to ongoing 3-week infusions with amivantamab. Second, many patients receive a cycle of chemotherapy while waiting for their next-generation sequencing results. In those patients, it makes much more sense to simply add osimertinib rather than asking if they want to switch treatments entirely to amivantamab plus lazertinib.”

Regarding safety, a patient-level, head-to-head toxicity comparison presented at the 2025 WCLC showed higher rates of grade 3 or higher adverse effects (AEs) with amivantamab plus lazertinib vs osimertinib plus chemotherapy (OR, 1.68; 95% CI, 1.21-2.34; P = .0022), as well as higher rates of serious AEs (OR, 1.56; 95% CI, 1.15-2.13; P = .0052).6 Rates of treatment discontinuation due to AEs were comparable (OR, 0.91; 95% CI, 0.56-1.50; P = .7064).

Panelists also identified the management of dermatologic AEs associated with amivantamab as a practical concern. Data from the phase 2 COCOON trial (NCT06120140) presented at the 2025 WCLC revealed that patients who received an enhanced prophylactic regimen experienced a significantly lower incidence of grade 2 or higher dermatologic AEs during the first 12 weeks vs those who received standard dermatologic management (42% vs 75%; OR, 0.24; 95% CI, 0.13-0.45; P < .0001).7 This benefit was consistent across most anatomic sites.

The panelists supported proactive toxicity mitigation, but noted that extensive patient education and prolonged infusion chair time remain barriers to the widespread adoption of amivantamab in community practice.

“Maybe we should be thinking about dose reduction from the get-go,” Sonam Puri, MD, the clinical research medical director at Moffitt Cancer Center in Tampa, Florida, said. “We don’t start anyone [on treatment] without the COCOON and [phase 2] SKIPPirr [(NCT05663866) regimens] …but even after the first dose, some patients say they never want to receive this drug again. Because of that first cycle, I don’t even get to have the conversation about interrupting and resuming. It’s just ‘one and done’ for many of my patients.”

How should treatment options be sequenced after first-line progression on osimertinib?

The panelists shifted the focus of their conversation to discuss the optimal sequencing of available regimens following progression on frontline osimertinib. Panelists agreed that amivantamab plus chemotherapy is generally preferred in the second-line setting, an approach that is supported by findings from MARIPOSA-2.

In this study, patients who received amivantamab plus chemotherapy after progression on osimertinib (n = 131) experienced a numerical OS benefit compared with chemotherapy alone (n = 263), with an HR of 0.73 (95% CI, 0.54-0.99; P = .039).8 The 18-month OS rates were 50% (95% CI, 40%-59%) and 40% (95% CI, 33%-46%), respectively.

Additional data from the phase 3 COMPEL trial (NCT04765059), also presented at the 2025 WCLC, demonstrated that continuation of osimertinib with platinum-based chemotherapy after progression improved outcomes.9 Patients who received osimertinib plus cisplatin or carboplatin with pemetrexed (n = 49) achieved a median PFS of 8.4 months (95% CI, 5.7-11.8) compared with 4.4 months (95% CI, 3.5-5.6) in those receiving placebo plus chemotherapy (n = 49; HR, 0.43; 95% CI, 0.27-0.70). The 6-month PFS rates were 64% and 32%, respectively.

“For MARIPOSA-2, the OS data are immature and not statistically significant,” Weiss noted. “If the COMPEL results show a significant OS [improvement], I would feel—having been an early adopter—more comfortable with COMPEL than MARIPOSA-2 after osimertinib monotherapy.”

“The fight was between MARIPOSA and FLAURA2,” Puri concluded. “Now, the fight is going to be between MARIPOSA-2 and COMPEL.”

References

Addressing the most critical treatment questions in EGFR-mutant advanced NSCLC.An OncLive Scientific Interchange and Workshop. OncLive. September 7, 2025. Accessed December 18, 2025.

FDA approves osimertinib with chemotherapy for EGFR-mutated non–small cell lung cancer. FDA. Updated February 20, 2024. Accessed September 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract PL02.06.

FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. Updated August 20, 2024. Accessed September 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer

Yang JCH, Lu S, Hayashi H, et al; MARIPOSA Investigators. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. Published online September 7, 2025. doi:10.1056/NEJMoa2503001

Resuli B, Kauffmann-Guerrero D, Mertsch P, et al. Redefining tolerability: a head-to-head IPD toxicity comparison of amivantamab+lazertinib vs osimertinib+chemotherapy in EGFR-mutant NSCLC. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.67.

Cho BC, Li W, Spira AI, et al. Enhanced vs standard dermatologic management with amivantamab-lazertinib in EGFRm advanced NSCLC: the COCOON global RCT. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.46.

Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non–small cell lung cancer after disease progression on osimertinib: second interim overall survival from MARIPOSA-2. Ann Oncol. 2024;35(suppl 2):S1244-S1245. doi:10.1016/j.annonc.2024.08.2296

Pasello G, Zhao J, Tufman A, et al. COMPEL: osimertinib + platinum-based chemotherapy in patients with EGFRm advanced NSCLC and progression on 1L osimertinib. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA08.03.