First-line osimertinib plus chemotherapy outperforms osimertinib monotherapy in the treatment of patients with advanced NSCLC harbouring EGFR mutations
Osimertinib is the preferred first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) harbouring EGFR mutations (EGFRm). The results of the FLAURA2 trial, recently presented at WCLC2023, revealed that combining osimertinib with chemotherapy improves progression-free survival compared to osimertinib monotherapy, together with a manageable safety profile. These results support osimertinib plus chemotherapy as a new first-line treatment option for patients with advanced EGFRm NSCLC.
Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are the standard of care for the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC) harbouring EGFR mutations (EGFRm). Despite their efficacy, most patients will progress following treatment. Factors like the presence of central nervous system (CNS) metastases or L858R mutations are associated with the poor prognosis of these patients. Osimertinib, a third-generation, CNS active EGFR-TKI, is the preferred first-line treatment for EGFRm advanced NSCLC based on the superior progression-free and overall survival (PFS/OS) benefit obtained with osimertinib vs. comparator EGFR-TKIs in the FLAURA study. The combination of osimertinib plus platinum-pemetrexed chemotherapy recently showed encouraging activity in the phase 2 OPAL study in patients with untreated EGFRm advanced NSCLC. However, this combination has not been evaluated in a randomised trial. To address this gap, the FLAURA2 study assessed the efficacy and safety of osimertinib plus platinum-pemetrexed vs. osimertinib monotherapy as first-line treatment for EGFRm advanced NSCLC.
Methods
The phase 3 FLAURA2 study included patients with untreated locally advanced/metastatic EGFRm non-squamous NSCLC, Ex19del/L858R mutations and no prior systemic/EGFR-TKI treatment for advanced NSCLC. The presence of stable CNS metastases was allowed. In total, 551 patients were randomly assigned (1:1) to receive osimertinib plus chemotherapy (osimertinib 80 mg once daily [QD] + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5 for four cycles every three weeks [Q3W]), followed by maintenance with osimertinib 80 mg QD + pemetrexed 500 mg/m2 Q3W (n=276) or osimertinib monotherapy (80 mg QD, n=275) until progression of disease or discontinuation. The primary endpoint was PFS. Secondary endpoints included OS, objective response rate (ORR) and safety.
Results
After a median follow-up of more than sixteen months for PFS, the median PFS was improved by 8.8 months with osimertinib plus chemotherapy compared to osimertinib alone (25.5 vs. 16.7 months, respectively; HR[95%CI]: 0.62[0.49-0.79]; p <0.0001). PFS rates were 80% vs. 66% for the combination and osimertinib alone at the 12-month landmark, respectively, and these were 57% vs. 41% at 24 months. The PFS benefit of the combination was consistent across pre-defined subgroups, including patients with different mutations (Ex19del or L856R) or CNS status at baseline. In patients with CNS metastases at baseline, the median PFS was 24.9 vs. 13.8 months with the combination and osimertinib alone, respectively (HR: 0.47). This was 27.6 vs. 21.0 months in patients without CNS metastases at baseline (HR: 0.75). Regarding the type of EGFR mutation, median PFS was 27.9 vs 19.4 months in patients with Ex19del treated with the combination or osimertinib alone, respectively (HR: 0.60). Patients harbouring an L858R alternation displayed a median PFS of 24.7 vs. 13.9 months, respectively (HR: 0.63). Both PFS2 and OS were immature at this point. However, PFS2 was longer in the combination compared to osimertinib monotherapy (30.6 vs. 27.8 months, respectively; HR[95%CI]: 0.70[0.52-0.93]; p=0.0132). Median OS was not reached in any of the groups (HR: 0.90; p=0.5238). ORR was 83% vs. 76% in the combination and monotherapy arms, respectively. The median best percentage change in target lesion size was similar in the combination and osimertinib monotherapy arms (-52.6% vs. -50.0%, respectively). However, the duration of response was longer in the combination arm (24.0 vs. 15.3 months in the monotherapy arm).
The safety profiles were as expected for each treatment and were manageable with standard medical practice. Adverse events (AEs) grade ≥3 possibly related to treatment were observed in 53% vs. 11% of patients in the combination and monotherapy groups, respectively. Most of the AEs in the combination arm were related to chemotherapy toxicity, including haematologic toxicities and nausea. All-grade interstitial lung disease (ILD) was reported in 9 patients (3%) in the osimertinib plus platinum-pemetrexed arm and 10 patients (4%) in the osimertinib monotherapy arm.
Conclusions
Osimertinib plus chemotherapy demonstrated a statistically significant and clinically meaningful PFS benefit over osimertinib monotherapy, with a manageable safety/tolerability profile. Based on these findings, osimertinib plus platinum-pemetrexed offers a new first-line treatment option for patients with EGFRm advanced NSCLC.
Reference
Janne P, et al. Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2). Presented at WCLC 2023; Presentation PL02.13.
