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Osimertinib as first-line therapy in advanced NSCLC: a profile of its use.

ABSTRACT: Osimertinib (Tagrisso®) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR TKI-activating mutations over wild-type EGFR in patients with advanced non-small cell lung cancer (NSCLC), including the T790M mutation that often underlies acquired resistance to earlier generation EGFR TKIs. Relative to standard of care first-generation EGFR TKIs (erlotinib or gefitinib) as first-line treatment of EGFR activating mutation-positive advanced NSCLC, osimertinib significantly prolongs median progression-free survival (PFS), with separation of the Kaplan-Meier PFS survival curves evident by the first assessment timepoint of 6 weeks. Osimertinib prolongs PFS relative to standard EGFR TKI therapy in all prespecified groups, irrespective of the EGFR mutation present at study entry and presence of CNS metastases at study entry. Overall survival data are not yet mature. Osimertinib has a generally manageable tolerability profile.

SUBMITTER: Scott LJ

PROVIDER: S-EPMC6300577 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Project description:BackgroundIn the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC).ObjectiveThe FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125).MethodsFLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint.ResultsAll 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified.ConclusionsFirst-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib.Clinical trial registrationClinicalTrials.gov NCT02296125, registered 20 November 2014.

Project description:The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR-TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of the combined regimen in the entire unselected population and selected patients by EGFR-mutation status and smoking history were calculated. Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR?=?0.81, 95% CI 0.69-0.95, P?=?0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P?=?0.02). In selected patients by EGFR-mutation, both mutation positive (HR?=?0.48, 95% CI 0.28-0.83, P?=?0.009) and negative (HR?=?0.84, 95% CI 0.72-0.98, P?=?0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P?=?0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR?=?0.51, 95% CI 0.35-0.74, P?=?0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status. Severe anorexia (RR?=?2.01, 95% CI 1.11-3.63; P?=?0.02) and diarrhea (RR?=?2.70, 95% CI 1.94-3.76; P<0.001) were more frequent in the combined regimen arm. This strategy of combining EGFR-TKIs and chemotherapy deserved to be considered in the future, although it is not approved for advanced NSCLC at the moment.

Project description:Although the advent of molecular-targeted drugs has improved the prognosis of various cancers, the long-term prognosis and side effects as the first-line therapy for metastatic choroidal tumors remain unclear. We describe a case in which the first-line therapy of osimertinib has shown long-term successful and minimum side effect responses for metastatic choroidal tumors in a patient with advanced-stage lung cancer. The patient was a 62-year-old man who complained of foggy vision and visual field defects in his left eye for 1 month. When he visited his local doctor, a serous retinal detachment was noted in the left eye, and he was referred to our hospital for further examination. The patient had no history of systemic disease. A fundus examination of his left eye showed a slightly elevated choroidal lesion along with the superior retinal vascular arcade. Optical coherence tomography showed a serous retinal detachment around the lesion. Fluorescein angiography showed that the site of the lesion had spotty and mottled hyperfluorescence in the early phase and ring hypofluorescence in the late phase. We suspected a metastatic choroidal tumor and performed a whole-body computed tomography scan, which indicated lung cancer and metastasis to the left iliac bone. The patient was referred to the department of respiratory medicine of our hospital, and after a thorough examination, a diagnosis of lung adenocarcinoma (stage IV-B, epidermal growth factor receptor [EGFR] gene mutation positive) was made. Treatment with osimertinib was initiated, and shrinkage of the primary tumor was observed. The elevated choroidal lesion and serous retinal detachment resolved after 2 months of treatment, and no recurrence was observed during the 20 months of treatment. The use of osimertinib as primary treatment for EGFR mutation-positive lung cancer was found to significantly reduce the size of metastatic choroidal tumors and to have a relatively long-lasting antitumor effect without serious ocular complications.

Project description:IntroductionAlthough programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized.MethodsIn this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT.ResultsAmong 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38).ConclusionsIn advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.

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Osimertinib as first-line therapy in advanced NSCLC: a profile of its use.

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