Osimertinib plus chemo-therapy: A promising 1L option for high-risk EGFRm NSCLC

The treatment landscape for EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC) is rapidly evolving, with many exciting developments on the horizon. At a recent scientific symposium, experts in lung cancer gathered to review the latest advances. This article highlights the key takeaways from the symposium, summarizing FLAURA2 trial data presented by Professor Natalia Valdiviezo from San Ignacio de Loyola University, Lima, Peru, and main insights from the panel discussion led by Dr Herbert Loong from the Department of Clinical Oncology, the Chinese University of Hong Kong, with contributions from Dr James Ho of the Department of Medicine, University of Hong Kong, and Dr Michael Kam, Specialist in Clinical Oncology in Hong Kong.

Osimertinib monotherapy: Current standard-of-care 1L treatment
“Osimertinib is one of the most im­portant third-generation EGFR tyrosine kinase inhibitors [TKIs] and the current guideline-recommended first-line [1L] treatment for advanced-stage EGFRm NSCLC,” said Valdiviezo. [Ann Oncol 2025:S0923-7534(25)00923-8]

In the pivotal phase III FLAURA study (n=556), osimertinib demonstrat­ed significant improvements in both progression-free survival (PFS) and overall survival (OS). Osimertinib’s median PFS was 18.9 months vs 10.2 months with first-generation EGFR TKIs (gefitinib or erlotinib) (hazard ratio [HR], 0.46; 95 per­cent confidence interval [CI], 0.37–0.57; p<0.001). Median OS also favoured osimertinib, at 38.6 vs 31.8 months (HR, 0.80; 95 percent CI, 0.64–1.00; p=0.046). These results were reported in a popula­tion of patients with common EGFR mu­tations, including exon 19 deletions. [N Engl J Med 2020;382:41-50; N Engl J Med 2018;378:113-125]

High unmet need in 1L setting, especially among high-risk patients
Despite these encouraging results, significant unmet need remains, as FLAURA data revealed that only 28 per­cent of patients treated with osimertinib were still on treatment at 3 years. Fur­thermore, a real-world study involving 1,323 EGFRm NSCLC patients treated with 1L osimertinib showed that medi­an real-world OS was approximately 10 months shorter than median OS in FLAURA. [N Engl J Med 2020;382:41-50; J Thorac Oncol 2025:1268-1278]

Importantly, nearly all patients (95 percent) in the real-world study had ≥1 high-risk feature: 17 had an Eastern Co­operative Oncology Group performance status (ECOG PS) ≥2, 36 percent had brain metastases, 15 percent had liver metastases, and TP53 co-mutation was present in 63 percent. Risk of death was significantly higher in patients with high-risk factors (p≤0.011 for all). In high-risk subgroups, median real-world OS was 18.1 months in patients with Eastern Co­operative Oncology Group performance score ≥2, 24.3 months in patients with brain metastases, 19.3 months in pa­tients with liver metastases, and 25.7 months in those with TP53 co-mutation. These findings underscore a pressing need for improved 1L options, particu­larly for patients with high-risk features.

Clinical features with poorer prognosis in EGFRm NSCLC
“While the OS benefits of 1L osim­ertinib in FLAURA were observed across various subgroups, this benefit was less pronounced for patients with central nervous system [CNS] metastases and L858R, suggesting these clinical charac­teristics are associated with poorer prog­nosis and reduced response to therapy,” pointed out Valdiviezo. [N Engl J Med 2020;382:41-50]

Supporting this, real-world data indi­cate that patients with brain metastases, liver metastases, TP53 co-mutations, and L858R mutations are at higher risk of shorter OS. These high-risk features are common among patients with EGFRm NSCLC, with approximately 36 percent having brain metastases, 15 percent having liver metastases, 48 percent carrying the L858R mutation, and 63 percent harbouring TP53 co-mutations. [J Thorac Oncol 2025:1268-1278]

Combination strategy: 1L option to improve survival outcomes
The phase III, open-label, random­ized FLAURA2 study (n=557) included treatment-naïve patients with EGFRm (exon 19 deletion or L858R mutation) advanced NSCLC. The study found that osimertinib combined with che­motherapy (pemetrexed–platinum) re­sulted in significantly longer PFS per investigator assessment (25.5 vs 16.7 months; HR, 0.62; 95 percent confi­dence interval [CI], 0.49–0.79; p<0.001) and per blinded independent central review (BICR) (29.4 vs 19.9 months; HR, 0.62; 95 percent CI, 0.48–0.80) vs osimertinib monotherapy after a median follow-up of 19.5 months. “Median PFS per BICR was improved by 9.5 months with combination therapy vs monother­apy,” highlighted Valdiviezo. (Figure 1) [N Engl J Med 2023;389:1935-1948]

In addition to the PFS benefit, 1L osimertinib plus chemotherapy demon­strated a significant OS benefit of nearly months vs osimertinib monothera­py (47.5 vs 37.6 months; HR, 0.77; 95 percent CI, 0.61–0.96; p=0.02) after a median follow-up of 51 months. (Figure 2) [N Engl J Med 2025;doi:10.1056/NE­JMoa2510308]

Notably, statistically significant PFS improvement was observed in FLAURA2’s Asian cohort (n=333) with combination therapy vs monotherapy, with a 31 percent reduction in risk of progression or death (median PFS, 25.5 vs 19.4 months; HR, 0.69; 95 percent CI, 0.51–0.94), which was consistent with the global population. [Yang JCH, et al, ESMO Asia 2024]

While the exact mechanisms are still being investigated, it is thought that osimertinib’s highly selective EGFR TKI activity combined with the nonselective antitumour effect of chemotherapy may overcome intratumour heterogeneity, elic­iting an additive effect by means of killing different cell populations, ultimately im­proving clinical outcomes. [N Engl J Med 2023;389:1935-1948]

Survival benefits in patients with high-risk features
FLAURA2 demonstrated that the PFS and OS benefit with osimertinib plus che­motherapy was consistent across almost all of the predefined subgroups, including patients with baseline CNS metastases and those harbouring L858R mutations. [N Engl J Med 2023;389:1935-1948]

“Specifically, patients with CNS me­tastases experienced a PFS of 24.9 months with combination therapy vs 13.8 months with osimertinib alone [HR, 0.47; 95 percent CI, 0.33–0.66], representing an approximately 11-month improve­ment and a 53 percent reduction in risk of progression or death. In contrast, among patients without CNS metasta­ses, although the PFS benefit was pres­ent, it was less pronounced [27.6 vs 21.0 months; HR, 0.75; 95 percent CI, 0.55–1.03], which confirms the combination’s particular benefit within the CNS metasta­ses subgroup,” Valdiviezo noted.

PFS benefit with osimertinib plus che­motherapy was also unequivocally demon­strated in patients with L858R mutations, who had a median PFS of 24.7 months vs 13.9 months among those treated with osimertinib monotherapy (HR, 0.63; 95 percent CI, 0.44–0.90). Patients with liver metastases also showed longer median PFS with combination treatment (19.5 vs 11.1 months; HR, 0.66; 95 percent CI, 0.41–1.07). [N Engl J Med 2023;389:1935- 1948; Valdiviezo N, et al, WCLC 2024]

Preliminary analysis of baseline tissue suggested that the PFS benefit of osim­ertinib plus chemotherapy vs osimertinib alone appeared to be similar regardless of the presence of baseline TP53 co-muta­tions. [Yang J, et al, WCLC 2024]

Implications for clinical practice
The results from FLAURA2 expand 1L treatment options for patients with EGFRm NSCLC. Combining osimertinib with chemotherapy not only enhances PFS and OS, particularly in high-risk pa­tient populations, but also suggests a new paradigm in EGFRm NSCLC man­agement.

“Risk stratification and establishing patients’ treatment preferences is import­ant,” said Ho. “Some patients prefer oral treatment only; I would discuss the po­tential treatment options with them and explain the benefits of TKI plus chemo­therapy.”

“We have OS data now, but it is a shared decision-making process,” agreed Kam. “I tend to select patients with high tumour burden and brain metastases for the combination treatment. Such patients are unlikely to receive chemotherapy in the second line, so it ought to be used upfront.”

One of the symposium attendants re­marked that using the FLAURA2 regimen, which has a reported objective response rate of 83 percent, may be beneficial in patients with superior vena cava obstruc­tion, and may help avoid radiotherapy, which may otherwise jeopardize bone marrow reserve and reduce the pa­tient’s ability to tolerate subsequent my­elosuppressive treatment. [N Engl J Med 2023;389:1935-1948]

Safety data on osimertinib plus chemotherapy
The safety profile of osimertinib com­bined with platinum–pemetrexed was consistent with the established profiles of each individual agent. In FLAURA2, the median duration of treatment was 22.3 months for the combination therapy vs 19.3 months with osimertinib monother­apy. While the combination regimen led to overlapping toxicities, primarily driven by chemotherapy-induced bone marrow suppression resulting in increased haematological adverse events (AEs), such as anaemia, neutropenia, and thrombocytopenia, these did not raise new safety signals and were manage­able with standard medical practice. [N Engl J Med 2023;389:1935-1948]

The severity and frequency of AEs were highest during the induction pe­riod and gradually declined over time. Notably, grade ≥3 AEs were reduced by 50 percent in 49 percent of patients within 3 months, and in 24 percent of patients within 3–9 months. Worsening of fatigue and appetite loss observed at the end of induction in the osim­ertinib plus chemotherapy arm was not deemed clinically meaningful and tended to improve during the main­tenance phase. Importantly, patient-reported outcome data demonstrated minimal impact on overall quality of life and symptoms with the addition of chemotherapy to osimertinib, support­ing the tolerability of the combination regimen. [Planchard D, et al, ESMO 2023; Lee CK, et al, ELCC 2024]