Exploring the impact of patient‐specific clinical features on osimertinib effectiveness in a real‐world cohort of patients with EGFR mutated non‐small cell lung cancer

Abstract

Osimertinib is prescribed to patients with metastatic non‐small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan‐Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR‐mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first‐line (40%), second‐line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4‐19.3), 13.9 (95% CI: 11.3‐16.1) and 8.7 months (95% CI: 4.6‐12.7), respectively. Patients with low BMI (<20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13‐4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45‐0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36‐0.92). A trend towards longer PFS was seen for TP53 wild‐type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC

“…Patients included in the current study were previously described in other studies evaluating different research questions, but the specific question whether plasma levels are associated with BM outcomes was not evaluated. 18 , 19 , 20 , 21 We think that our study adds to the available literature. Furthermore, we did not use the proposed cutoff of C min 166 ng/mL, because we found that a large proportion of our patients had a C min above this value.…”

“…This study was approved in each center (MUMC+; 2019-1080, NKI/AvL; IRBd19-192 and IRBdm20-218, ErasmusMC; 16-643, START-TKI; NCT05221372). Samples from patients included in this study were previously evaluated for other research questions by Van Veelen et al., 18 Agema et al., 19 Boosman et al., 20 and Veerman et al.. 21 All patients signed informed consent. Patients who underwent a dose reduction of osimertinib during treatment were excluded from the analyses, because the found plasma C min,SS would not be representative for the total time of osimertinib treatment.…”

“…Osimertinib plasma samples were included in the analysis if (1) the plasma sample was taken within 6 to 36 hours after the last osimertinib intake, because the maximum plasma concentration is reached after approximately 6 hours; (2) the plasma sample was taken at least 15 days after start osimertinib (steady state); (3) blood withdrawal took place at least 3 months before progression, because an increase of the osimertinib plasma concentration was found shortly before progression. 18 When multiple eligible samples per patient were available, the average C min,SS of these samples was calculated and used in further analyses.…”

“…HR was adjusted for sex, line of treatment, EGFR mutation, and TP53 status, as those were known to have an impact on osimertinib survival outcomes. 18 , 26 The median follow-up time was calculated using the reversed Kaplan-Meier analysis. All statistical analyses were performed with the software package SAS version 9.4 (SAS Institute).…”

“…No differences were found between patients with a low (<568 nM [284 ng/mL]) versus those with a high (≥568 nM [284 ng/mL]) osimertinib C min,SS , but it should be noted that the median osimertinib C min,SS found in this Japanese cohort was substantially higher than what would be expected in a White population (approximately 200 ng/mL as reported by Rodier et al.). 16 , 17 , 18 …”