APPLE is a 3 arms phase II non-comparative trial exploring the sequential treatment approach of gefitinib followed by osimertinib or osimertinib frontline in patients with advanced EGFR-mutant NSCLC. Here we report the exploratory analysis of the outcome with osimertinib frontline compared to a sequential approach.
Patients were randomized to: arm A (osimertinib until RECIST progression -PD-), arm B (gefitinib until the emergence of circulating tumor DNA EGFR T790M mutation or RECIST PD) or arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms B and C. In this analysis, arms B and C were pooled. Primary endpoint: Progression Free Survival rate “on osimertinib” at 18 months (PFSR-OSI-18) in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints: overall survival (OS) and Brain PFS (BPFS). Primary analyses were performed in per-protocol population (PPP). In all arms, contrast-enhanced brain CT-scan was performed every 8 weeks.
From 11/2017 to 02/2020, 156 patients were randomized (arm A:53, arm B/ C:103), and 136 were included in the PPP. Most patients were females (56.6% and 69.9%), with EGFR Del19 (66% and 64%). Baseline brain metastases: 19% and 29.1%, respectively. In pooled arms B/C, 70% of patients received osimertinib at PD. In arm A, PFS on osimertinib was 19.5 months. The PFSR-OSI-18 was 51.1% in Arm A and 61% in pooled arms B/C. The median OS was NR in arm A vs 42.8 (95% CI: 28.6-NR) months (mo) in pooled arm B/C, with 18-months OS of 84.4% and 82.3%, respectively. In all arms, 68 brain progression events were observed. Median time to brain PD in arm A and B/C were 34.3 mo (95% confidence interval, CI:26.9-NR) and 22.3 mo (95%CI:18.6–22.3), and corresponding hazard ratio was 0.54 (90% CI: 0.34–0.86) with 18-months BPFS of 82.2% and 63.5%, respectively.
In advanced EGFR mutant-NSCLC, upfront treatment with osimertinib shows a significant reduction in the risk of brain progression, with comparable OS versus the sequential treatment approach.
NCT02856893.
EORTC.
AstraZeneca.
J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, Pfizer, MSD, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, Takeda, Sanofi; Financial Interests, Personal, Expert Testimony: OSE Immunotherapeutics; Non-Financial Interests, Personal, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD; Non-Financial Interests, Personal, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca; Non-Financial Interests, Personal, Member, Secretary of the Lung Cancer Group at the EORTC: EORTC. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai pharmaceutical, Eisai, Inivata, Ipsen, Turning Point Therapeutics. L. Greillier: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, BMS, MSD, Novartis, Sanofi, Takeda, Roche; Financial Interests, Personal, Invited Speaker: Eli Lilly, Pfizer, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, AbbVie, BMS, MSD, Novartis, Sanofi, Takeda, Pfizer, PharmaMar. N. Reguart Aransay: Financial Interests, Personal, Advisory Board: Roche, MSD, Takeda, Bayer, Novartis, Sanofi, Janssen, AstraZeneca, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Boehringer Ingelheim, Guardant, BMS, Pfizer, Amgen, Novartis. I. Monnet: Other, Personal, Other, invitation to virtual ASCO 2021 and 2022: Pfizer; Other, Personal, Other, invitation to ESMO congress 2021 and 2022: Takeda. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Sanofi, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen; Financial Interests, Personal, Other, Data monitoring committee for INC280I12201 trial in 2020: Novartis; Financial Interests, Personal, Invited Speaker, CACZ885V2201C_CANOPY-N trial: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Invited Speaker, IO102-012/KN-764 trial: IO Biotech; Financial Interests, Personal, Invited Speaker, JNJ-61186372 (JNJ-372) Clinical Development Program: Janssen; Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairFellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumours: ESMO; Non-Financial Interests, Personal, Leadership Role, President of the Spanish Federation of Medical Societies (FACME) 2020-2022Past President 2023-2024: FACME; Non-Financial Interests, Personal, Leadership Role, Former President of Spanish Medical Oncology Society: SEOM; Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (AECC) and also Board member: AECC; Non-Financial Interests, Personal, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member: IASLC; Non-Financial Interests, Personal, Advisory Role, Member of the Spanish National Health Advisory Board: Spanish Minister of Health; Non-Financial Interests, Personal, Advisory Role, Assessment for lung cancer screening evaluation: EUnetHTA; Non-Financial Interests, Personal, Advisory Role: Spanish National Evaluation network (RedETS); Non-Financial Interests, Personal, Advisory Role, scientific advisory group member for clinical immunological, oncology and lung cancer areas: EMA; Other, Personal, Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind of relationship with TEVA: TEVA. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, Amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Eli Lilly, Janssen, Pfizer, AstraZeneca, Eli Lilly, Amgen, Daiichi Sankyo, Roche, Roche, JNJ, Mirati; Financial Interests, Institutional, Research Grant: Amgen; Non-Financial Interests, Personal, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Personal, Member: IASCL, ASCO, AACR. All other authors have declared no conflicts of interest.