Osimertinib plus platinum–pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study

Abstract

Background The phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum–pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation. Patients and methods Patients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m 2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m 2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m 2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib–chemotherapy combination. Results Thirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib–carboplatin–pemetrexed, 100%; osimertinib–cisplatin–pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib–carboplatin–pemetrexed and nausea (60%) with osimertinib–cisplatin–pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable. Conclusions Osimertinib–chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

The efficacy and tolerability of combining pemetrexed-based chemotherapy with gefitinib in the first-line treatment of non-small cell lung cancer with mutated EGFR: A pooled analysis of randomized clinical trials

“…In the FLAURA2 trial, osimertinib plus pemetrexed and platinum chemotherapy was administered to achieve a higher efficacy and longer survival. The safety run-in results reported a manageable safety and tolerability profile for the combination therapy [ 22 ]. In detail, the most common treatment-related adverse event was constipation (60%), and 20% of enrolled patients suffered serious treatment-related adverse events [ 22 ].…”

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

“…Whether chemotherapy can delay the development of resistance to third-generation EGFR-TKIs remains unknown. A study on osimertinib with or without chemotherapy as first-line therapy for patients with EGFR-mutant NSCLC is currently recruiting (NCT04035486) [ 210 ].…”

Acquired Resistance to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer: How Do We Overcome It?

“…The ongoing phase III trial FLAURA2 compares first-line osimertinib plus a platinumpemetrexed based chemotherapy with osimertinib alone in EGFR-mutated NSCLC. The first results published encouragingly demonstrated manageable safety and tolerability of this combination [86]. Additionally, a study designed to prevent SCLC transformation is combining platinum-etoposide chemotherapy plus osimertinib in the first-line setting for EGFR-mutated NSCLC with concurrent RB1 and TP53 mutations (NCT03567642).…”