<BACKGROUND>
Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported.
<METHODS>
In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point.
<RESULTS>
The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P=0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.
<CONCLUSIONS>
Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125. opens in new tab.)
To the Editor: In the FLAURA trial update, Ramalingam and colleagues (Jan. 2 issue)1 present data regarding overall survival with first-line osimertinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), as compared with one of two other EGFR-TKIs (gefitinib and erlotinib), in patients with mutation–positive advanced non–small-cell lung cancer (NSCLC), regardless of T790M mutational status. The median overall survival was 38.6 months in the osimertinib group and 31.8 months in the comparator group.
In 2017, the AURA3 trial showed superior progression-free survival for osimertinib over platinum-based therapy (10.1 months vs. 4.4 months) in patients with T790M mutations who had disease progression after first-line treatment with EGFR-TKIs.2 Previously, Maemondo et al.3 found that the use of the first-generation EGFR-TKI gefitinib resulted in longer overall survival than chemotherapy (30.5 months vs. 23.6 months) in previously untreated patients with EGFR-mutated cancers. Therefore, given the survival benefits shown in these two trials, patients in whom T790M mutations develop while they are receiving first-generation EGFR-TKIs theoretically could have an overall survival of more than 40 months with second-line osimertinib if the therapies were sequenced correctly. Furthermore, whether the survival benefit of first-line osimertinib relates to T790M mutational status is still unknown. It is unclear whether patients who participated in the FLAURA trial were tested for the presence of the T790M mutation during enrollment. Also, there was no subgroup analysis of overall survival in the 47% of patients in the comparator group who crossed over to receive osimertinib, results that could have been masked by a different second subsequent therapy.
The question of the most effective sequencing of available therapies is paramount to oncologists. It seems possible that first-line osimertinib may disadvantage the approximately 50% of patients in whom T790M mutations develop and who would benefit more from sequential osimertinib.4
Kelvin Yan, M.D.
University of Oxford, Oxford, United Kingdom
To the Editor: The recent trial by Ramalingam et al. showed the superior efficacy of the EGFR-TKI osimertinib over comparator EGFR-TKIs for the treatment of NSCLC. Similar results were reported earlier for the progression-free survival of these patients.1 However, despite the better responses, a high percentage of patients with this type of cancer die or have disease progression.
In the subgroup analyses, the authors describe notable differences in the response to osimertinib between Asian and non-Asian patients, with more pronounced effects of osimertinib among non-Asian patients.1 The effect of EGFR polymorphisms on EGFR-TKI efficacy has been described previously,2 and it is likely that differences in genetic polymorphisms in various ethnic groups will influence EGFR-TKI efficacy. A recent network meta-analysis also suggested that interethnic differences in genetic polymorphisms may influence the efficacy of osimertinib.3 Differences in allele frequencies and linkage disequilibrium between Asian and non-Asian patients are present in the EGFR locus, and additional polymorphisms can further influence the efficacy of EGFR-TKI treatment. Furthermore, such interethnic differences have been shown to correlate with the EGFR mutational pattern.4 In future studies, it will be important to focus on population-associated genetic determinants that affect the efficacy of current EGFR-TKI treatments.
To the Editor: Despite an initial period of good response, most EGFR-mutated pulmonary adenocarcinomas progress with time. The poor penetrability of older drugs into the central nervous system (CNS) often means that a substantial proportion of failures happen in the CNS.1 Even before the publication of the results of the FLAURA trial,2 osimertinib has been noted because of its more extensive CNS penetration than either gefitinib or erlotinib.
It would be of immense clinical value if Ramalingam et al. could provide us with the following information: First, what was the CNS failure rate among patients without previous CNS metastases in the osimertinib group and in the comparator group? Second, was the between-group separation in the curves for progression-free survival among the patients with CNS metastases greater than the separation in the general population? And third, what was the overall survival for patients with brain metastases in the two treatment groups?
The authors reply: In response to the comments by Yan: approximately 30% of patients in the two treatment groups (including those who died) did not receive a second-line therapy after discontinuation of the trial drug. As noted in the Discussion section of our article, the EGFR T790M resistance mutation develops in approximately 50% of the patients who receive an earlier-generation EGFR-TKI, which creates a biologically driven limit to the number of patients who are eligible to benefit from second-line osimertinib. Of the patients in the comparator group who received a second-line therapy, 47% received osimertinib as a T790M-directed therapy. The median overall survival that we observed in the comparator group was among the highest reported for EGFR-mutated NSCLC, which is at least in part attributable to the crossover from the comparator group to receive osimertinib. The use of osimertinib resulted in an overall survival benefit over the comparator EGFR-TKIs despite this crossover. In our trial, de novo T790M mutations were detected in only five patients (four in the osimertinib group) at baseline,1,2 which would not account for the benefit in progression-free survival and overall survival observed with osimertinib. Therefore, osimertinib is the preferred first-line therapy to provide all patients with the opportunity to benefit.
In response to the comments by Staege: progression-free survival is the best direct measure of efficacy, and we have previously reported longer progression-free survival with osimertinib than with a comparator EGFR-TKI (hazard ratio, 0.46; P<0.001), a difference that was also observed across all predefined subgroups, including Asian and non-Asian subgroups.2 Overall survival encompasses subsequent lines of therapy, and multiple factors may influence the margin of improvement, including differences in local clinical practice, ethnic differences in metabolism of EGFR-TKIs, and ethnic sensitivity to subsequent therapies. The suggested analysis of EGFR polymorphisms and their influence on EGFR-TKI efficacy may shed further light on this topic and merits further investigation.
In response to Revannasiddaiah and colleagues: patients in the osimertinib group had a 52% lower risk of CNS progression than the comparator group (hazard ratio, 0.48; P=0.01); CNS response rates were numerically higher with osimertinib.3 We have also reported that among the patients with no known or treated CNS metastases at trial entry, CNS progression occurred in 7 patients (3%) in the osimertinib group and in 15 patients (7%) in the comparator group.2 In our final overall survival analysis, subgroup data show that the hazard ratios for death were similar between patients with CNS metastases at trial entry and those without such metastases.
