FLAURA2: Osimertinib-chemo prolongs OS by 4 years in EGFRm NSCLC

In the planned final overall survival (OS) analysis of the FLAURA2 trial, first-line (1L) osimertinib plus chemotherapy significantly improved OS compared with osimertinib alone in EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC), supporting osimertinib as the backbone treatment in this setting.

“[After a median follow-up of 51 months,] 1L osimertinib + chemo demonstrated superior OS over osimertinib monotherapy, with a median OS of 47.5 months – the longest in a global phase III study showing OS benefit in this population,” said study investigator Dr David Planchard from the Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France, during his presentation at WCLC 2025.

This was 10 months longer than that observed for osimertinib monotherapy (37.6 months). A comparison between arms yielded a hazard ratio (HR) of 0.77 (p=0.02). The OS probability at 4 years with the experimental regimen was 49 percent as opposed to 41 percent with osimertinib only. [WCLC 2025, abstract PL02.06]

To put these further into context, these findings mean that almost half of the participants in the combination arm were alive at 4 years, Planchard noted.

Moreover, the OS probability favouring the combination over the monotherapy regimen was sustained from that reported at 2 (80 percent vs 72 percent) and 3 years (63 percent vs 51 percent).

The OS benefit was consistent across all predefined subgroups, including patients with brain metastasis and L858R mutation. The most pronounced effect was observed among non-Asians (HR, 0.56).

Other outcomes

Importantly, the combination arm had a long chemo-free period, with median total exposures of 2.8 months for platinum, 8.3 months for pemetrexed, and 30.5 months for osimertinib. In the comparator arm, median total osimertinib exposure was 21.2 months.

“This means that the median duration of osimertinib exposure was over three times longer than [that with] pemetrexed maintenance,” Planchard explained.

The combination regimen continued to demonstrate manageable safety and tolerability despite the longer duration of exposure, which was consistent with the established profiles of the individual agents.

With over 2 years of additional follow-up since the primary analysis, no new safety signals were observed, nor were there new treatment-related deaths in the osimertinib + chemo arm. One death was reported in the osimertinib monotherapy arm. According to Planchard, the safety profiles remain as expected and manageable.

The incidence of adverse events (AEs) leading to osimertinib discontinuation remained low in both the investigational and comparator arms (12 percent vs 7 percent). The most common grade 3 AE with the combination regimen was anaemia (20 percent), followed by neutropenia (11 percent) and a decrease in neutrophil count (9 percent).

Chemo was the most common first subsequent treatment (FST) in both the combination and monotherapy arms (69 percent and 77 percent). In the combination arm, 44 percent of FSTs were rechallenge with platinum chemo. “The OS benefit in the combination arm was observed despite standard-of-care (SoC) chemo being the most common FST after osimertinib monotherapy,” said Planchard.

Compelling OS data support primary results

A total of 557 patients (median age 62 years, 62 percent women) were randomized 1:1 to receive osimertinib 80 mg QD with or without chemo. In the experimental arm, osimertinib was administered on top of pemetrexed 500 mg/m² and investigator’s choice of carboplatin AUC5 or cisplatin 75 mg/m² Q3W for four cycles during the induction phase. The maintenance phase ensued thereafter, wherein participants received osimertinib plus pemetrexed at the same doses and schedules as in the induction phase.

Two-thirds of the participants were Asian. Of these, a quarter were Chinese, and about 40 percent were non-Chinese. The most frequent EGFR mutation type was Ex19del (60 percent), while the rest had the L858R type. Almost all (96 percent) had metastatic disease, and 41 percent had central nervous system metastases at baseline. The final OS analysis was conducted at 57 percent maturity.

In the primary analysis, the investigational regimen demonstrated a progression-free survival benefit vs osimertinib alone (HR, 0.62; p<0.001). [N Engl J Med 2023;389:1935-1948] This led to its subsequent approval, and guidelines have since recommended this combo regimen as a treatment alternative in this patient setting. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer; https://ascopubs.org/doi/10.1200/JCO-24-02785, accessed September 29, 2025]

“The compelling OS results confirm osimertinib + chemo as 1L SoC in EGFRm advanced NSCLC,” Planchard concluded.

Next steps

“What’s interesting in FLAURA2 is that, despite the median chemo exposure of up to 8 months, we do see a prolonged effect on subsequent resistance, and this raises the question of whether dose intensity does matter throughout … I think this remains a question that we want to answer, particularly when combining with a reasonable SoC to optimize some of the side effect profiles,” noted discussant Professor Daniel Tan from Duke-NUS Medical School, Singapore, at WCLC 2025.

Furthermore, considering the distinct mechanisms of action of combination therapies, Tan highlighted that discovering biomarkers and identifying populations who may benefit from specific combination therapies are key priorities.

Tan added that shared decision-making based on individual preferences or priorities is going to be key. “Hopefully, we can work together as a community to build a GPS-enabled map of EGFRm lung cancer and other oncogenic drivers so that we can really tailor these individual approaches.”