Upfront osimertinib may reduce the risk of brain progression in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), according to results from the APPLE trial.
The risk of progression in the brain was 46% lower in patients who received upfront osimertinib than in those who received gefitinib followed by osimertinib. However, there was no difference in progression-free survival (PFS) or overall survival (OS) between the groups.
These results were presented at the European Lung Cancer Congress 2023 by Jordi Remon, MD, PhD, of Institut Gustave Roussy in Villejuif, France.
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Dr Remon explained that the phase 2 APPLE trial (ClinicalTrials.gov Identifier: NCT02856893) was designed to determine the best sequence of treatment with gefitinib and osimertinib and to see if circulating tumor DNA (ctDNA) testing for the T790M mutation could guide the switch from gefitinib to osimertinib.
The trial included 156 patients with advanced, EGFR-mutant NSCLC who had not previously received an EGFR tyrosine kinase inhibitor. The patients were randomly assigned to 3 treatment arms:
- In arm A, 53 patients received osimertinib at 80 mg daily until disease progression.
- In arm B, 52 patients received gefitinib at 250 mg daily until they became EGFR T790M-positive or had progressive disease according to RECIST criteria. Then, they received osimertinib at 80 mg daily until disease progression.
- In arm C, 51 patients received gefitinib at 250 mg daily until disease progression according to RECIST criteria, followed by osimertinib at 80 mg daily until disease progression.
Dr Remon compared results with upfront osimertinib (arm A) to results with sequential gefitinib and osimertinib (arms B and C together, n=103). The median age was 68 (range, 46-87) years in the upfront osimertinib arm and 65 (range, 31-89) years in the sequential therapy arm. Brain metastasis was seen in 19% of patients in the upfront osimertinib arm and 29% of those in the sequential therapy arm.
In the upfront osimertinib arm, 20 patients received treatment after progression, including chemotherapy (50%), osimertinib (15%), targeted therapy (15%), radiotherapy (15%), and other treatment.
In the sequential treatment arm, 81 patients received treatment after progression, including osimertinib on study (82%), osimertinib off study (6%), targeted therapy (10%), and other treatment.
The primary endpoint was PFS at 18 months, and there was no significant difference between the arms. The 18-month PFS rate was 51% in the upfront osimertinib arm and 61% in the sequential therapy arm (hazard ratio [HR], 0.87; 90% CI, 0.60-1.26). The median PFS was 19.5 months and 21.39 months, respectively.
However, the risk of progression in the brain was significantly lower in patients who received osimertinib upfront. The median brain PFS was 34.3 months in the upfront osimertinib arm and 22.3 months in the sequential therapy arm. The 18-month brain PFS rate was 82.2% and 63.5%, respectively (HR, 0.54; 90% CI, 0.34-0.86).
OS results were comparable between the arms. The median OS was not reached for the upfront osimertinib arm and was 42.8 months for the sequential therapy arm. The 18-month OS rate was 84.4% and 82.3%, respectively (HR, 1.01; 90% CI, 0.61-1.68).
The rate of grade 3 or higher adverse events (AEs) was 39.6% in the upfront osimertinib arm and 28.2% in the sequential therapy arm. The rate of grade 3 or higher treatment-related AEs was 7.5% and 7.0%, respectively.
The most common treatment-related AEs of any grade (in the upfront osimertinib arm and sequential arm, respectively) were diarrhea (39.6% and 23.9%), dry skin (37.7% and 12.7%), and acneiform rash (20.8% and 9.9%).
Dr Remon said this trial showed that upfront osimertinib can reduce the risk of brain progression but produces comparable OS as gefitinib followed by osimertinib. The trial also showed that serial ctDNA monitoring of T790M status is feasible, and a lack of ctDNA clearance on EGFR tyrosine kinase inhibitor therapy may reveal a population of patients who could benefit from escalation treatment strategies.
Disclosures: This research was supported by AstraZeneca. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Reference
Remon Masip J, Ponce Aix S, Callejo Perez A, et al. Osimertinib versus gefitinib followed by osimertinib in patients with EGFR-mutant non-small cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE trial. ELCC 2023. March 29 – April 1, 2023. Abstract 1O.
