FLAURA2 post-progression outcomes

Since the publication of the FLAURA study, osimertinib has become the standard of care in the first line treatment of patients with EGFR-mutant metastatic NSCLC. Last year, however, the presentation of the randomized, phase III FLAURA-2 trial challenged this standard, by showing a significantly longer progression-free survival when using a combination of osimertinib and chemotherapy in first line instead of osimertinib alone. Importantly, however, this benefit in PFS did come at the cost of considerable toxicity.

During the 2024 European Lung Cancer Conference (ELCC), Prof Dr Natalia Valdiviezo Lama, medical oncologist at the Instituto Nacional de Enfermedades Neoplásicas in Surquillo, Peru, presented updated results of FLAURA-2, with a focus on post progression outcomes. In the absence of mature overall survival data, intermediate endpoints looking at the time to the start of subsequent treatment lines and subsequent progressions give an indication on the long-term treatment benefits of osimertinib-chemotherapy.

In FLAURA-2 trial, 557 patients with EGFR-mutant, non-squamous NSCLC who were not previously treated with a systemic therapy in the advanced setting were randomly assigned to receive osimertinib plus chemotherapy, or osimertinib alone. In previous reports of this trial, the osimertinib-chemotherapy combination proved to be associated with a 38% reduced risk for disease progression or death compared to osimertinib alone (median PFS 25.5 vs. 16.7 months; HR[95%CI]: 0.62[0.49-0.79]; p< 0.001). Of note, the benefit in PFS obtained with the osimertinib-chemotherapy combination was particularly pronounced in patients with brain metastases (HR[95%CI]: 0.47[0.33-0.66]).

From the FLAURA-2 update presented at ELCC 2024 it became clear that the benefit in PFS seen with osimertinib-chemotherapy translated into a significantly longer time to the first (HR[95%CI]: 0.73[0.56-0.94]) and second (HR[95%CI]: 0.69[0.51-0.93]) subsequent line of therapy. A closer look at the patients who received a second line treatment learns that chemotherapy was the most common treatment choice across both treatment arms. Interestingly, also the time to the second disease progression (PFS2) was significantly longer with osimertinib-chemotherapy compared to osimertinib alone (median 30.6 vs 27.8 months; HR[95%]: 0.70[0.52-0.93]).

At an overall maturity of 41%, a non-significant trend for a better overall survival was reported in favour of the chemotherapy-osimertinib combination with a 3-year OS rate of 64% as compared to 50% in patients who only received osimertinib in 1^st line (HR[95%CI]: 0.75[0.57-0.97], p= 0.028 with a boundary of significance of ≤0.000001).

For Prof Valdiviezo Lama, future research should focus on the identification of biomarkers or clinical features that allow a better selection of patients who benefit most from the osimertinib-chemotherapy combination. This would allow physicians to intensify the treatment in the subgroup of patients that needs it, while sparing patients who are unlikely to derive a benefit from chemotherapy from unnecessary toxicity.