A phase 3, international, open-label, randomized clinical trial has found that first-line treatment with osimertinib plus chemotherapy significantly improved progression-free survival compared to osimertinib alone in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC). The study, known as FLAURA2, was funded by AstraZeneca and published in the New England Journal of Medicine on November 23, 2023.
The purpose of the study was to evaluate whether adding chemotherapy to osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, could extend the benefits of EGFR-TKI therapy in the first-line treatment of EGFR-mutated advanced NSCLC. Osimertinib is currently the preferred first-line treatment for this patient population based on previous trials showing superior efficacy compared to first-generation EGFR-TKIs. However, most patients eventually develop disease progression on osimertinib monotherapy, creating a need for strategies to further improve outcomes.
The FLAURA2 trial enrolled 557 patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutations who had not previously received systemic treatment for advanced disease. Patients were randomized 1:1 to receive either osimertinib (80 mg once daily) plus pemetrexed (500 mg/m2) and carboplatin or cisplatin chemotherapy, or osimertinib monotherapy (80 mg once daily). The primary endpoint was investigator-assessed progression-free survival.
Key inclusion criteria were pathologically confirmed nonsquamous NSCLC with local or central confirmation of EGFR exon 19 deletion or L858R mutation, World Health Organization (WHO) performance status score of 0 or 1, and no prior systemic treatment for advanced disease. Patients with stable central nervous system (CNS) metastases were eligible. The study population had a median age of 61-62 years, was predominantly female (61-62%), and had a high proportion of Asian patients (63-64%). Notably, 41% of patients had CNS metastases at baseline and 53% had extrathoracic metastases.
The results showed that osimertinib plus chemotherapy significantly prolonged progression-free survival compared to osimertinib alone. The median progression-free survival was 25.5 months in the combination therapy group versus 16.7 months in the monotherapy group (hazard ratio 0.62; 95% CI 0.49-0.79; p<0.001). The 24-month progression-free survival rate was 57% with combination therapy compared to 41% with monotherapy. These findings were consistent in a blinded independent central review.
The objective response rate was higher with combination therapy (83%) than monotherapy (76%). Importantly, the median duration of response was substantially longer in the combination group at 24.0 months versus 15.3 months with monotherapy. The combination therapy showed consistent benefits across key subgroups, including patients with CNS metastases and those with L858R mutations - populations that historically have poorer outcomes.
While the interim overall survival analysis was immature at 27% data maturity, it indicated that adding chemotherapy to osimertinib did not appear detrimental to survival. The hazard ratio for death was 0.90 (95% CI 0.65-1.24). Longer follow-up will be needed to determine if the progression-free survival benefit translates to an overall survival advantage.
As expected, the combination regimen was associated with a higher incidence of adverse events, particularly hematologic toxicities related to chemotherapy. Grade 3 or higher adverse events occurred in 64% of patients receiving combination therapy compared to 27% with monotherapy. The most common grade 3-4 adverse events with combination therapy were anemia (20%), neutropenia (14%), and thrombocytopenia (7%). Gastrointestinal side effects like nausea, decreased appetite, and vomiting were also more frequent with the combination.
Despite the increased toxicity, the combination therapy appeared manageable, with similar osimertinib dose intensity maintained in both groups. The safety profile was consistent with the known effects of the individual agents, with no new safety signals identified. Adverse events leading to discontinuation of osimertinib occurred in 11% of patients on combination therapy versus 6% on monotherapy.
The authors concluded that first-line osimertinib plus platinum-pemetrexed chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy in patients with EGFR-mutated advanced NSCLC. They noted that while the combination increased toxicity, particularly hematologic adverse events, the safety profile was consistent with the established profiles of the individual agents.
This study had several strengths, including its large sample size, international patient population, and use of both investigator and blinded independent assessments. The trial also included a high proportion of patients with CNS metastases (41%), allowing for robust evaluation in this important subgroup. However, there were some limitations to consider. As an open-label study, there is potential for bias in investigator assessments, though this was mitigated by the blinded independent review showing consistent results. Additionally, the study only included patients with common EGFR mutations (exon 19 deletion or L858R), so the results may not be generalizable to those with uncommon EGFR mutations.
The FLAURA2 results have potentially significant clinical implications for the first-line treatment of EGFR-mutated advanced NSCLC. The substantial improvement in progression-free survival and duration of response with combination therapy may lead to changes in treatment guidelines and clinical practice. The combination of osimertinib plus platinum-pemetrexed chemotherapy could become a new standard first-line option, particularly for patients with characteristics associated with poorer prognosis like CNS metastases or L858R mutations.
However, the increased toxicity of the combination regimen will need to be carefully weighed against the efficacy benefits for individual patients. The lack of mature overall survival data also leaves some uncertainty about the long-term impact of this approach. Ongoing follow-up from this trial, as well as real-world evidence, will be important to further clarify the role of this combination strategy.
Additionally, the results raise interesting questions about the optimal sequencing of targeted therapy and chemotherapy in EGFR-mutated NSCLC. While this study evaluated concurrent administration, future research may explore other approaches like sequential therapy or intermittent dosing schedules to potentially improve the balance of efficacy and toxicity.
In conclusion, the FLAURA2 trial provides compelling evidence that adding platinum-pemetrexed chemotherapy to osimertinib can significantly extend progression-free survival in the first-line treatment of EGFR-mutated advanced NSCLC. While associated with increased toxicity, this combination approach represents a promising new option to improve outcomes for patients with this molecularly defined subtype of lung cancer. As with any practice-changing study, the results will need to be carefully interpreted and applied in the context of individual patient factors and preferences. Nonetheless, FLAURA2 marks an important advance in the ongoing efforts to optimize targeted therapy strategies for EGFR-mutated NSCLC.
References
Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
