LBA51 - Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial

Background

APPLE is a randomized, non-comparative, open-label, 3-arm, phase II study in patients with common EGFR-mutant, treatment-naïve NSCLC, aimed to evaluate the feasibility of longitudinal plasma EGFR T790M monitoring and the best sequencing strategy from gefitinib to osimertinib.

Methods

We report the results of arm B (gefitinib until the emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR Test v2 or progression (PD) by RECIST) and arm C (gefitinib until PD by RECIST), and then switch to osimertinib in both arms. Primary endpoint is Progression Free Survival rate (by RECIST 1.1) “on osimertinib” at 18 months (PFSR-OSI-18). The study was designed to reject a PFSR-OSI-18 of ≤40% in Arm B with 1-sided α = 0.08 and 92% power under a PFSR-OSI-18 of 60%. Arm C was an internal control arm. Secondary endpoints: response rate, overall survival (OS) and Brain PFS (BPFS). The primary analysis was performed in per-protocol (PP) population.

Results

From Nov 2017 to Feb 2020, 52 and 51 patients in 6 countries were randomized to Arm B and C. Most patients were females (75% and 65%), never smokers (71% and 59%) and had EGFR Del19 (64% and 65%), respectively. Median age was 69 and 61 years. One-third of patients had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on ctDNA T790M-positive before RECIST PD. Median follow-up was 30 months. The study met its primary endpoint - PFSR-OSI-18 was 67.2% (84%CI 56.4-75.9%) in arm B vs. 53.5% (84% CI 42.3-63.5%) in arm C, with a median PFS of 22.0 months (95% CI 18.6-NR) vs. 20.2 months (95% CI 14.6-35.0), respectively. The median OS was not reached in arm B vs. 42.8 months (95%CI 27.0-NR) in arm C. Median BPFS in arm B and C were 24.4 months (95% CI 17.9-28.6) and 21.4 months (95% CI 14.5-42.8). Toxicity was as expected for both drugs.

Conclusions

Serial monitoring of ctDNA T790M status in patients with advanced EGFR mutant-NSCLC by Cobas v2.0 PCR test treated with first-generation EGFR inhibitors is feasible, and a molecular progression before RECIST PD led to earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

European Organization for Research and Treatment of Cancer (EORTC).

Funding

AstraZeneca.

Disclosure

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, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD; Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): Astra-Zeneca. 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: 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, Astra-Zeneca; Financial Interests, Personal, Invited Speaker: Astra-Zeneca, MSD, Boehringer, Guardant, BMS, Pfizer. I. Monnet: Other, Other, invitation to virtual ASCO 2021 and 2022: Pfizer; Other, Other, invitation to ESMO congress 2021 and 2022: Takeda. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Novartis, IO Biotech; 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 a clinical trial in 2020: 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, study entitled JNJ-372: Janssen; Non-Financial Interests, 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, Leadership Role, President of the Spanish Federation of Medical Societies (FACME): FACME; Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind of relationship with Teva: Teva; Non-Financial Interests, Leadership Role, Former President of Spanish Medical Oncology SocietyMember of the Spanish National Health Advisory Board: SEOM; Non-Financial Interests, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Borad member: AECC; Non-Financial Interests, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member: IASLC. M.R. Garcia Campelo: Financial Interests, Personal, Invited Speaker: BMS, Jansen, Takeda, pfizer, roche, AstraZeneca, novartis, lilly, AstraZeneca, Jansen; Financial Interests, Personal, Advisory Board: MSD, Jansen, Sanofi, Takeda, BMS, roche, pfizer, AstraZeneca, novartis, lilly. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Lilly, Jansen, Pfizer, AstraZeneca, Lilly, Amgen, Daiichi, Roche, Roche, JNJ, Mirati; Financial Interests, Institutional, Research Grant: Amgen; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. R. Dziadziuszko: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, SeattleGenetics, Pfizer, Takeda, Regeneron, MSD, Bristol Myers-Squibb, PharmaMar, Bayer; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, FoundationMedicine; Financial Interests, Personal, Expert Testimony: Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Roche, AstraZeneca, MSD, Amgen, Celon Pharma, Pfizer, Novartis, Brsitol Myers-Squibb, Eli Lilly, Loxo; Financial Interests, Invited Speaker: BeiGene, Ardigen, OSE Immunotherapeutics; Financial Interests, Personal and Institutional, Other, Subinvestigator and ad hoc Consultant: PDC* line Pharma; Non-Financial Interests, Institutional, Product Samples: Novartis, Pfizer, AstraZeneca, Roche; Other, Travel: Roche, Bristol Myers-Squibb, AstraZeneca. All other authors have declared no conflicts of interest.