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Overall Survival Outcomes of Patients With Advanced EGFR-Mutant NSCLC Receiving Osimertinib vs Gefitinib Followed by Osimertinib
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A clinical trial update was reported from the phase II APPLE trial, wherein patients with EGFR-mutant advanced non–small cell lung cancer (NSCLC) were treated with first-line osimertinib upfront (arm A) or with sequential treatment using gefitinib upfront followed by osimertinib at progression (either detection of a resistance mutation or radiologic progression; arms B and C, respectively). The median overall survival was not reached in arm A and was 42.8 months in arms B and C pooled. The median time to brain progressive disease was 34.3 months in arm A and 22.3 months in arms B and C pooled. Notably, there was a higher proportion of patients with baseline brain metastases in arms B and C than in arm A.
- In the APPLE trial, upfront treatment with osimertinib was associated with a lower rate of brain progression in patients with EGFR-mutant advanced NSCLC; however, overall survival was comparable between the treatment groups.
abstract
This abstract is available on the publisher's site.
Access this abstract nowClinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.
Osimertinib has been established as a standard of care for patients with common sensitizing EGFR-mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR-mutant NSCLC.
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Overall Survival From the EORTC LCG-1613 APPLE Trial of Osimertinib Versus Gefitinib Followed by Osimertinib in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer
J. Clin. Oncol 2024 Feb 07;[EPub Ahead of Print], J Remon, B Besse, SP Aix, A Callejo, K Al-Rabi, R Bernabe, L Greillier, M Majem, N Reguart, I Monnet, S Cousin, P Garrido, G Robinet, RG Campelo, A Madroszyk, J Mazières, H Curcio, B Wasąg, Y Pretzenbacher, F Grillet, AC Dingemans, R DziadziuszkoFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The randomized phase II APPLE trial previously demonstrated a respectable 18-month progression-free survival rate with sequential gefitinib followed by osimertinib, which rivaled that of first-line (1L) osimertinib for patients with classical, sensitizing EGFR-mutant advanced non–small cell lung cancer (NSCLC).1 In this manuscript, Remon et al present the results of a secondary endpoint — overall survival (OS) — among patients treated with 1L osimertinib (arm A) versus those treated with sequential gefitinib/osimertinib (arms B + C combined). Although the risk for CNS progression was higher with the sequential approach (HR, 1.84; 90% CI, 1.16 –2.93), the OS outcomes were no different between the sequential arm and 1L osimertinib arm (OS HR, 1.01; 90% CI, 0.61–1.68).
The phase III FLAURA trial2 was a practice-changing study, which demonstrated a significant OS advantage with osimertinib compared with a first-generation (gen1) EGFR tyrosine kinase inhibitor (TKI) for treatment-naïve advanced EGFR-mutant NSCLC. Despite later-line osimertinib being the preferred treatment for patients with T790M-mediated progression on a gen1 TKI, which occurs in 50% to 60% of these patients, the effective crossover rate in the FLAURA trial was only around 30%. Although the response rates are lower than those in patients with T790M positivity, osimertinib can have efficacy in the T790M-negative population based on prior clinical trial and real-world data. In the APPLE trial, T790M positivity was not a requirement for second-line (2L) osimertinib after gefitinib. With effectively approximately 80% of the patients in the sequential arm crossing over to osimertinib, these results suggest that osimertinib may be good enough in T790M-negative patients to potentially nullify the OS benefit of 1L osimertinib seen in the FLAURA trial.
In regions of the world where 1L gen1 EGFR TKIs have remained the standard of care, 2L osimertinib may be considered even in patients without detection of T790M-mediated resistance. Otherwise, osimertinib should remain the standard TKI used in treatment-naïve patients with classical EGFR-mutant metastatic NSCLC. With less wild-type EGFR inhibition than gen1/2 inhibitors, the toxicity profile of osimertinib is preferable. Also, APPLE demonstrates that CNS penetration remains a significant advantage of osimertinib over gen1/2 TKIs, and delaying brain progression in patients is an important outcome. For this trial, quality-of-life metrics with 1L osimertinib versus sequential gefitinib/osimertinib would be interesting and may also favor osimertinib for toxicity and CNS control. We must remember that this was a noncomparative study, and the present results are for a secondary endpoint (OS); yet, this unique, complex trial offers a wealth of information to be explored further in future clinical trials.
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