NEWS & PERSPECTIVE
FDA approves the addition of chemotherapy to osimertinib in EGFRm advanced lung cancer
Osimertinib is a third-generation, orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) previously approved for the first-line treatment of EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC).1,2 Results from the phase 3 FLAURA trial showed that osimertinib significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to first-generation EGFR TKIs in EGFRm NSCLC patients.1,2 In the phase 3 FLAURA2 trial, osimertinib plus chemotherapy significantly extended the PFS over osimertinib alone among patients with EGFRm NSCLC, opening the door for its approval by the United States (US) Food and Drug Administration (FDA).1,3
NSCLC is the most common type of lung cancer and is associated with poor prognosis.2 In approximately 20% of Caucasian patients and 40% of Asian patients with NSCLC, tumor growth is driven by mutations in the EGFR gene.2 EGFR TKIs are the first-line treatment for patients with NSCLC harboring EGFR-sensitizing mutations as they bind irreversibly to these tumors, inhibiting mutant kinase activity.2,4 As patients tend to acquire resistance to first- and second-generation TKIs, mediated by the EGFR T790M mutation, third-generation EGFR TKIs such as osimertinib were developed to overcome these resistance mechanisms.2,4
However, despite the therapeutic efficacy of osimertinib, many patients still experience disease progression after approximately 15-20 months.1,4 Recognizing the improvement in the addition of chemotherapy to earlier generations of TKIs, the phase 3 FLAURA2 trial was designed to replicate these benefits with osimertinib.1 The phase 3 FLAURA2 trial thus sought to assess the efficacy and safety of osimertinib plus platinum-pemetrexed as compared with osimertinib monotherapy in patients with EGFRm NSCLC.1 In this international, open-label trial, 557 treatment-naïve patients with EGFRm (exon 19 deletion or L858R mutation), advanced NSCLC were randomized 1:1 to receive osimertinib alone or with chemotherapy (pemetrexed plus cisplatin or carboplatin).1 The primary endpoint was investigator-assessed progression-free survival (PFS), while response and safety were also assessed.1
Investigator-assessed PFS was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (median PFS: 25.5 months vs. 16.7 months; HR=0.62; 95% CI: 0.49-0.79, p<0.001) and similar results were observed when PFS was assessed according to blinded independent central review (BICR) (HR=0.62, 95% CI: 0.48-0.80).1 At 24 months, 57% (95% CI: 50-63) of patients were alive and progression-free in the osimertinib-chemotherapy group, compared to the 41% (95% CI: 35-47) observed in the osimertinib group, respectively.1 Moreover, the PFS benefit was consistent across subgroups defined according to EGFR mutation type and the presence or absence of central nervous system (CNS) metastases at baseline, including patients with L868R mutations or CNS metastases which are factors associated with poorer prognosis.1
The objective (complete or partial) response rate was also higher in the osimertinib-chemotherapy group compared to osimertinib alone (83% vs. 76%) and the median response duration was also longer [24.0 months (95% CI: 20.9-27.8] vs. 15.3 months (95% CI: 12.7-19.4)].1 Adverse events (AEs) of grade 3 or higher were reported in 64% of patients in the osimertinib-chemotherapy group compared to 27% in the osimertinib group.1 The higher incidence of hematologic toxicities (71% vs. 24%) was attributed to chemotherapy-induced bone marrow suppression.1 Additionally, gastrointestinal adverse events such as nausea, decreased appetite, constipation and vomiting were also more common in the osimertinib-chemotherapy group.1
In summary, osimertinib plus chemotherapy led to a significant prolongation of PFS by approximately 8.8 months by investigator assessment compared to osimertinib alone.1 The safety profile of osimertinib plus chemotherapy was also consistent with the established profiles of the individual agents with no new safety concerns identified, offering a promising new therapeutic strategy for patients with EGFRm advanced NSCLC.1
