Osimertinib Plus Chemo Outperforms Single-Agent Osimertinib Regardless of Prognostic Factors in EGFR+ NSCLC

Consistent overall survival (OS) benefit with first–line osimertinib (Tagrisso) plus platinum-based chemotherapy across poor prognostic subgroups in the phase 3 (NCT04035486) FLAURA2 trial reinforce the use of this intensified regimen over osimertinib monotherapy as the standard of care in EGFR-mutated non–small cell lung cancer (NSCLC), according to Pasi A. Jänne, MD, PhD.1

Updated data from an exploratory OS analysis of the FLAURA2 trial presented at the 2025 ESMO Congress showed that HRs for OS favored the combination (n = 88) vs single-agent osimertinib (n = 143) in all 6 prognostic subgroups evaluated. In patients presenting with baseline central nervous system (CNS) metastases, the median OS was 40.9 months with the combination vs 29.7 months with osimertinib monotherapy (HR, 0.72). For those harboring an EGFR L858R mutation, the median OS was 38.1 months vs 32.4 months (HR, 0.76), respectively. The median OS was not reached vs 43.0 months for the exon 19 deletion group (HR, 0.76). Similarly, those with detectable plasma EGFR mutations achieved a median OS of 38.4 months vs 32.5 months (HR, 0.79). Patients harboring TP53 alterations saw OS improve from 43.1 months with monotherapy to 51.1 months with the combination (HR, 0.71).

“The benefit was more pronounced in the presence of one of these clinical or molecular prognostic features, but even in the absence of those prognostic features, the combination was better than the single agent,” Janne shared with OncLive®.

In the interview, Janne shared prior results from FLAURA2 that supported the February 2024 FDA approval of osimertinib plus chemotherapy for locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations2; insights from the exploratory OS analysis of this study; and the importance of informed patient decision-making when choosing between combination therapy and single-agent osimertinib.

Janne serves as the ​​senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, a senior physician, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute; as well as a professor of medicine at Harvard Medical School.

OncLive: How was the FLAURA2 trial designed, and what findings have been previously reported from the primary and final analyses?

Janne: FLAURA2 was a randomized trial in patients with advanced EGFR-mutant NSCLC in the first-line setting, comparing single-agent osimertinib with osimertinib and platinum-pemetrexed chemotherapy. The chemotherapy—platinum-pemetrexed—was administered for 4 cycles. The subsequent therapy was maintenance pemetrexed with osimertinib.

Prior data reported from this study showed that the combination of chemotherapy and osimertinib [n = 279] significantly improved progression-free survival [HR, 0.62; 95% CI, 0.49-0.79; P < .001] and OS [HR, 0.77; 95% CI, 0.61-0.96; P = .02] compared with single-agent osimertinib [n = 278] in EGFR-mutant NSCLC.3,4

What data from the exploratory OS analysis were presented at the 2025 ESMO Congress and how might these findings influence clinical decision-making in the first-line setting?

At the ESMO 2025 conference, we presented data looking at prognostic features that tend to be associated with poor prognosis. These features included clinical prognostic features, such as the presence of brain metastases, liver metastases, or bone metastases, as well as molecular prognostic features. Molecular features included the different common EGFR mutations (L858R or exon 19 deletion), the presence of a concomitant TP53 mutation at baseline, and the presence of baseline circulating tumor DNA.

The study demonstrated that regardless of the presence or absence of clinical or molecular poor prognostic features, [prolonged] survival [was observed] with osimertinib and platinum-pemetrexed compared with osimertinib alone.

How should the risks and benefits of frontline osimertinib plus chemotherapy be weighed against that of osimertinib monotherapy or the MARIPOSA combination of amivantamab-vmjw (Rybrevant) plus lazertinib in clinical practice, particularly with respect to second-line treatment sequencing and patient goals?

Both the [phase 3] MARIPOSA [NCT04487080] and FLAURA2 combinations show that an intensified regimen is better than single-agent osimertinib in terms of both PFS and OS. Those benefits are observed in both combination studies. It is an informed decision-making process with the patient to let them know what can be achieved clinically with a combination treatment, and at the same time explaining the added cost in terms of AEs, inconvenience, etc., that comes with that. Everybody needs to balance out what fits him or her, and it is a discussion we have quite frequently in the clinic.

In which scenarios might you still favor osimertinib monotherapy over the combination regimen for your patients?

We have certainly treated a number of patients with the combination. The combination therapy does have an increase in adverse effects [AEs] compared to osimertinib alone, as well as the inconvenience of having to come to the clinic for infusions every 3 weeks. For some patients, especially those who may travel from a far distance, that is too burdensome. As such, patients prefer the treatment with single-agent osimertinib.

References

1. Jänne PA, Planchard D, Kobayashi K, et al. FLAURA2: exploratory overall survival analyses in patients with poorer prognostic factors treated with osimertinib ± platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA77.
2. FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed October 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
3. Tagrisso plus chemotherapy demonstrated a median overall survival of nearly four years, the longest benefit ever reported in a global Phase III trial in EGFR-mutated advanced lung cancer. News release. AstraZeneca. September 7, 2025. Accessed October 27, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/tagrisso-plus-chemotherapy-demonstrated-a-median-overall-survival-of-nearly-four-years.html
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434