FLAURA2 post-progression outcomes

Previously presented results of the phase III FLAURA-2 trial have demonstrated a benefit in progression-free survival (PFS) with a first line combination of osimertinib and platinum-based chemotherapy compared to osimertinib alone in previously untreated patients with EGFR-mutant advanced NSCLC. Importantly, however, this benefit in PFS did come at the cost of a considerable toxicity. During the 2024 European Lung Cancer Conference (ELCC), updated results of this trial were presented with a focus on post progression outcomes. To discuss these findings, Prof Mariana Brandão, medical oncologist at the Institut Jules Bordet, was joined by Dr Kristof Cuppens, pulmonologist and thoracic oncologist at the Jessa Hospital in Hasselt.

In the phase III 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).

Commenting on these findings both Dr Cuppens and Prof Brandão indicate to be impressed by the favorable PFS2 and OS data. In fact, these findings indicate that combining both osimertinib and chemotherapy in first line is more effective than using these two treatment modalities consecutively. Should the osimertinib-chemotherapy become available, Dr Cuppens beliefs that it will be important to involve patients in the choice between osimertinib monotherapy or the combination with chemotherapy in first line. However, especially for patients with brain metastases, the combination strategy seems to be a very potent option. In their conclusion, both physicians underscore the need for biomarkers to allow for a better selection of patients who are likely to benefit from the chemotherapy-osimertinib combination. Finally, the availability of different therapeutic options with a variable treatment intensity creates the need for clinical trials that look into treatment escalation strategies and might facilitate a better treatment personalization.