Clinical trialPhase 3Lung cancerBrain tumours

CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer

JCO · 2018556 patients in the whole study; 128 patients with measurable and/or non-measurable CNS lesions on baseline imaging (200 patients with a brain scan at study entry)

Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et al. JCO. 2018. 36:3290-3297

Study type: Clinical trial
Study name: FLAURA
Phase: Phase 3
Design: Preplanned subgroup analysis of the randomised phase 3 FLAURA trial; the main objective of this analysis was central nervous system (CNS) progression-free survival
Sample size: 556 patients in the whole study; 128 patients with measurable and/or non-measurable CNS lesions on baseline imaging (200 patients with a brain scan at study entry)
Source: JCO · 2018

In plain words

This analysis looked at how well the drug osimertinib works on disease in the brain and central nervous system in patients with EGFR-mutated lung cancer who had not yet been treated. In patients with brain lesions, osimertinib lowered the risk of the disease growing in the brain compared with the standard tablets for this group (gefitinib or erlotinib), and more of the brain lesions responded to treatment. These results are encouraging, but treatment decisions should always be made with your treating doctor.

Key results

128 of 200 patients with a brain scan (osimertinib 61, standard EGFR-TKI 67)

Number of patients with CNS lesions on baseline imaging

Of these, 41 patients (22 in the osimertinib group and 19 in the standard EGFR-TKI group) had at least one measurable CNS lesion

Osimertinib: median not reached (95% CI 16.5 months to not calculable) vs 13.9 months (95% CI 8.3 months to not calculable) with standard EGFR-TKI

Median CNS progression-free survival (measurable and/or non-measurable lesions)

Hazard ratio 0.48 (95% CI 0.26 to 0.86); P = 0.014 (nominally significant)

91% vs 68% (osimertinib vs standard EGFR-TKI)

CNS objective response rate in patients with at least one measurable lesion

Odds ratio 4.6 (95% CI 0.9 to 34.9); P = 0.066

66% vs 43% (osimertinib vs standard EGFR-TKI)

CNS objective response rate in patients with measurable and/or non-measurable lesions

Odds ratio 2.5 (95% CI 1.2 to 5.2); P = 0.011

Consistently lower with osimertinib than with standard EGFR-TKI

Probability of CNS progression

Drugs in this study:Osimertinib (Tagrisso)

Dose and schedule cards

Osimertinib monotherapy (FLAURA)

Metastatic NSCLC with an EGFR exon 19 deletion or L858R (tissue or plasma sample); first-line. Also the T790M mutation after older-generation inhibitorsCycle length: ContinuousOn the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Metastatic NSCLC with an EGFR exon 19 deletion or L858R (tissue or plasma sample); first-line. Also the T790M mutation after older-generation inhibitors

Drug	Dose	Route	Schedule
Osimertinib	80 mg	Oral, with or without food (can be dispersed in water)	Once daily, continuous

Cycle length: Continuous
Duration: Until disease progression or intolerable toxicity

Source: FDA label; trial. Monitoring and dose modifications as for the adjuvant osimertinib regimen (ADAURA) (QTc, LVEF in patients with cardiac risk factors, permanent discontinuation for interstitial lung disease, 160 mg with a strong CYP3A4 inducer).

On the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Osimertinib

Osimertinib 80 mg orally once daily, until disease progression or unacceptable toxicity.

2Standard EGFR-TKIs

Gefitinib 250 mg or erlotinib 150 mg orally once daily, until progression or unacceptable toxicity; at progression with a T790M mutation, crossover to osimertinib was offered.

Source of the regimen details: FDA label for osimertinib (TAGRISSO, DailyMed; FLAURA trial section)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with previously untreated advanced EGFR-mutated non-small-cell lung cancer. Patients with asymptomatic or stable CNS metastases were enrolled. In patients with symptomatic CNS metastases, neurological status had to be stable for at least 2 weeks after completion of definitive treatment and corticosteroids. Brain scans were not mandatory unless clinically indicated. The subgroup analysis was performed in patients with measurable and/or non-measurable CNS lesions on the baseline brain scan (blinded independent central neuroradiological review). The evaluable-for-CNS-response set included patients with at least one measurable CNS lesion.

According to the FDA label: EGFR exon 19 deletion or L858R mutation, WHO PS 0 to 1; brain metastases not requiring steroids with stable neurological status for at least 2 weeks after completion of definitive surgery or radiotherapy were allowed.

Endpoints

Main objective of the subgroup analysis: CNS progression-free survival in patients with measurable and/or non-measurable CNS lesions on the baseline scan. Other reported outcomes: CNS objective response rate and probability of CNS progression.

Safety and side effects

Safety data are not reported in the abstract of this paper.

Clinical significance and place in guidelines

According to the abstract, osimertinib has CNS efficacy in untreated EGFR-mutated patients and reduces the risk of CNS progression compared with standard EGFR-TKIs. These findings support osimertinib as a first-line treatment option in patients with brain metastases. The exact status of approvals and clinical guideline recommendations should be checked separately, as the abstract does not mention them.

Limitations

This is a preplanned subgroup analysis, and brain scans at study entry were not mandatory; only 200 of 556 patients had a baseline brain scan and 128 had CNS lesions. The number of patients with measurable lesions was small (41), and in this subgroup the difference in objective response rate was not statistically significant (P = 0.066, with a wide confidence interval). The significance of CNS progression-free survival is reported as "nominal". The upper limit of the confidence interval for the median could not be calculated in either group.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.