Episode 2: The FLAURA2 trial
Presented by Prof Mariana Brandao (Institut Jules Bordet) and Prof Johan Vansteenkiste (University Hospitals Leuven)
Prof Mariana Brandao and Prof Johan Vansteenkiste discuss the FLAURA2 trial presented at WCLC2023, a recent study in EGFR-mutated NSCLC that holds clinical significance.
Osimertinib currently stands as the standard treatment for treatment-naïve patients with EGFR-mutated lung tumours, demonstrating high response rates at the first evaluation of the disease. However, resistance inevitably develops in all patients, irrespective of exon 19 or 21 deletion. Consequently, there is a quest for treatment optimization, with escalation trials being a potential avenue. In this context, platinum-based chemotherapy, a former gold standard, is added to osimertinib.
The FLAURA2 trial randomly assigns patients to receive either osimertinib alone or in combination with carboplatin or cisplatin (as per the investigator’s choice) and pemetrexed for four cycles, followed by maintenance with pemetrexed and osimertinib. The primary endpoint, PFS, demonstrated improvement from 16 to 25 months with the combined osimertinib and chemotherapy treatment, yielding a significant hazard ratio of 0.62.
A remarkable discovery from the trial, presented at ESMO2023, is that patients with brain metastases appear to derive the most benefit from the osimertinib and chemotherapy combination, reducing the risk of central nervous system progression. This is unexpected, challenging the long-held belief that chemotherapy has limited efficacy in the brain. However, it’s crucial to note that this insight stems from a subgroup analysis and was not part of the trial’s initial design.
Despite these positive aspects, concerns arise from the trial, such as the lack of significant benefits in PFS2 and the absence of a positive trend in OS. Therefore, while the study is intriguing and supports the concept of escalation, the necessity for biomarkers and specific patient selection is evident.
The experts note that the initial notion that TKIs could replace chemotherapy has not materialized. The addition of chemotherapy now raises concerns, particularly since no improvement in OS has been demonstrated. Experts acknowledge the positive trial findings but emphasize the importance of considering the patient’s perspective. The convenience of a daily tablet at home versus the need to visit the clinic every three weeks for chemotherapy administration presents a significant contrast.
The ongoing evolution of the trial is expected to provide more insights and QoL data will be crucial in determining the approach. If patients with chemotherapy experience lower intracranial progression, it may offset increased toxicity. Experts eagerly await pemetrexed maintenance rates, especially considering the tendency to stop earlier when combining immunotherapy and chemotherapy. Biomarkers, such as ctDNA, could play a role in decision-making. Starting with osimertinib monotherapy and evaluating clearance after six weeks to either add or not chemotherapy could be a biologically rational and more patient-friendly approach. In any case, the emphasis is on selecting patients who would benefit from escalation therapy, taking into account biomarkers and co-mutations. These findings, coupled with insights from other trials in a similar context, are expected to illuminate the most effective patient-directe
References:
Planchard D et al, 2023, FLAURA2: Safety and CNS outcomes of first-line (1L) Osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC. Annals of Oncology 34 (suppl_2): S1311-S1312
Janne P et al, 2023, Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2), WCLC2023 #PL03.13