A phase III FLAURA2 study shows that among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), first-line osimertinib plus chemotherapy with pemetrexed and a platinum-based agent was associated with a significant improvement in progression-free survival (PFS) according to investigator assessment, as compared with osimertinib monotherapy. The hazard ratio (HR) for disease progression or death in the analysis of PFS according to investigator assessment was 0.62 in favour of osimertinib plus chemotherapy and was consistent with the results of the assessment by means of blinded central independent review (BCIR).
The median prolongation in PFS with the combination as compared with monotherapy was approximately 8.8 months according to the investigator assessment and 9.5 months according to the BCIR. The findings are published by Dr. David Planchard of the Department of Medical Oncology, Institut Gustave Roussy in Villejuif, France, Dr. Pasi Jänne of the Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute in Boston, MA, US, and colleagues in the 23rd November 2023 issue of the NEJM.
The authors explained in the background that osimertinib is the preferred first-line treatment for patients with EGFR-mutated advanced NSCLC, based on the results from the phase III FLAURA study, which showed superior PFS and overall survival (OS) benefits with first-line osimertinib as compared with first-generation EGFR tyrosine kinase inhibitors (TKIs). However, despite the efficacy of first-line treatment with osimertinib, most patients will have disease progression.
Phase II and III studies have shown superior efficacy outcomes with the first-generation EGFR TKI gefitinib plus carboplatin-pemetrexed as compared with gefitinib alone. These data support the hypothesis that the addition of a platinum-based agent and pemetrexed to osimertinib may extend the benefit provided by osimertinib alone. Osimertinib is a third-generation EGFR TKI that is selective for EGFR TKI sensitising and EGFR T790M resistance mutations.
The phase III, international, open-label, randomised FLAURA2 study was designed in two phases: safety run-in and randomised phases. The safety run-in phase showed that osimertinib plus platinum-pemetrexed had a safety profile consistent with the safety profiles of its components without new side effects, findings that supported further assessment in the randomised phase. In the latest issue of NEJM, the study team reports efficacy and safety data for first-line osimertinib plus platinum-pemetrexed as compared with osimertinib monotherapy in patients with EGFR-mutated advanced NSCLC from the randomised phase of the FLAURA2 study.
In this phase III, international, open-label study, the study investigators randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC who had not previously received treatment for advanced disease to receive osimertinib once daily with chemotherapy consisting of pemetrexed plus either cisplatin or carboplatin or to receive osimertinib monotherapy once daily. The primary endpoint was investigator-assessed PFS. Response and safety were also assessed.
A total of 557 patients underwent randomisation. Investigator-assessed PFS was significantly longer in the osimertinib plus chemotherapy group than in the osimertinib group (HR for disease progression or death 0.62, 95% confidence interval [CI] 0.49 to 0.79; p < 0.001). At 24 months, 57% (95% CI 50 to 63) of the patients in the osimertinib plus chemotherapy group and 41% (95% CI 35 to 47) of those in the osimertinib group were alive and progression-free. PFS as assessed according to BCIR was consistent with the primary analysis (HR 0.62, 95% CI 0.48 to 0.80).
An objective (complete or partial) response was observed in 83% of the patients in the osimertinib plus chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI 20.9 to 27.8) and 15.3 months (95% CI 12.7 to 19.4).
The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy, a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.
At ESMO 2023 Congress in Madrid, Dr. Planchard reported that osimertinib with addition of chemotherapy showed consistent PFS benefit across patient subgroups and presented further the outcomes in patients with central nervous system (CNS) metastases at baseline by CNS BCIR. The addition of chemotherapy to osimertinib reduced the risk of CNS progression or death, increased CNS objective response rate, the proportion of patients achieving CNS complete response, and improved durability of CNS responses.
Dr. Planchard also reported that overall, the safety profiles were as expected for each treatment. The frequency and severity of adverse events were highest during platinum-based doublet induction chemotherapy, with a subsequent meaningful reduction over time.
In an accompanied editorial article published in the NEJM, Drs. Yi-Long Wu and Qing Zhou of the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University in Guangzhou, China wrote that these results are truly remarkable with a 9-month prolongation in PFS.
If OS is prolonged by osimertinib plus chemotherapy, the FLAURA2 strategy will be considered as standard first-line treatment for EGFR-mutated advanced NSCLC. However, if OS is not prolonged, patients receiving the combination treatment may have chemotherapy-related side effects earlier and for a longer period than those receiving monotherapy, which raises the question of appropriate sequencing of therapy.
The editorialists also underlined that the combination treatment in the FLAURA2 study will face a great challenge from new combinations. The MARIPOSA study of the third-generation TKI lazertinib with the bispecific antibody amivantamab has shown positive results, and the SANOVO study, which involves a combination of the two oral drugs osimertinib and savolitinib (a MET inhibitor) in patients with MET overexpression, is ongoing.
The FLAURA2 study was supported by AstraZeneca.
- Planchard D, Jänne PA, Cheng Y, et al. for the FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023; 389:1935-1948
- Wu Y-L, Zhou Q. Combination Therapy for EGFR-Mutated Lung Cancer. N Engl J Med 2023; 389:2005-2007
- LBA68 – Planchard D, Jänne PA, Cheng Y, et al. FLAURA2: Safety and CNS outcomes of first-line (1L) osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC. Annals of Oncology 2023;34 (suppl_2):S1311-S1312. DOI: https://doi.org/10.1016/j.annonc.2023.10.069