Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE)

NCT02856893 | Active Not Recruiting Phase 2 Results FDA Drug

• 2 other identifiers: EORTC-1613ESR-15-11406
• Study Type: interventional
• Target: 156
• Locations: 6 countries
• Sites: 23

Brief Summary

The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.

Conditions

NSCLC

Keywords

AZD9291; Osimertinib; Gefitinib; NSCLC; liquid biopsy; ctDNA

Outcome Measures

Primary Outcomes (1)

• PFS Rate at 18 Months

  The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI). Specifically, it relates to progression of disease according to RECIST 1.1 or death after switching to osimertinib in arms "Gefitinib till + blood test/progression then Osimertinib" and "Gefitinib till progression then Osimertinib". It is formally assessed in these two arms, whilst only provided as a reference for the "Osimertinib till progression" arm, in which progression of disease or death is measured from baseline considering that patients start with osimertinib.

  18 months after randomization

Secondary Outcomes (8)

• PFS While Receiving Osimertinib by RECIST Criteria 1.1

  From randomization till the date of progression on osimertinib or death, an average of 2 years.

• Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive

  From randomization till the date of positive cfDNA T790M status or death, on average 2 years.

• Time to Progression on Osimertinib

  From randomization till the date of progression on osimertinib or death, on average 2 years.

• Overall Response Rate (ORR) to Osimertinib

  Time from randomization until end of osimeritinib treatment, or death, on average 2 years.

• Treatment Duration

  From randomization till the date of end of protocol treatment

Study Arms (3)

Osimertinib till progression

EXPERIMENTAL

Osimertinib until PD according to RECIST 1.1

Drug: Osimertinib

Gefitinib till + blood test/progression than Osimertinib

EXPERIMENTAL

Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1

Drug: Osimertinib; Drug: Gefitinib

Gefitinib till progression than Osimertinib

ACTIVE COMPARATOR

Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1

Drug: Osimertinib; Drug: Gefitinib

Interventions

Osimertinib DRUG

Osimertinib 60 or 40 mg daily until progression

Also known as: AZD9291, Tagrisso

Gefitinib till + blood test/progression than Osimertinib; Gefitinib till progression than Osimertinib; Osimertinib till progression

Gefitinib DRUG

Gefitinib 250mg daily until progression

Also known as: Iressa

Gefitinib till + blood test/progression than Osimertinib; Gefitinib till progression than Osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Registration:
• Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory;
• Stage IV NSCLC;
• Blood sample available for cfDNA EGFR T790M central testing;
• Age ≥18 years;
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI;
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration;
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations
• Randomization:
• Report of adequacy sample for cfDNA EGFR T790M test by central laboratory;
• Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization;
• Patients with brain metastases are allowed provided they are stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization; Baseline tumor assessment scans are done within 21 days before randomization;
• Evaluable disease as defined below;
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
• WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks;

You may not qualify if:

• Treatment with any of the following:
• Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug;
• Prior treatment with an EGFR-TKI;
• Major surgery (excluding placement of vascular access) within 4 weeks before randomization;
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before randomization
• Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4;
• Other anti-cancer therapies and alternative medications such as homeopathic treatment, etc;
• Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known;
• Leptomeningeal carcinomatosis; spinal cord compression;
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 2 at the time of randomization;
• Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localised and presumed cured prostatic cancer) within 2 years before randomization and are not receiving specific treatment for these malignancies at baseline assessment;
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active infection will include any patients receiving intravenous treatment for infection; active hepatitis B infection will, at a minimum, include all patients who are Hepatitis B surface antigen positive (HbsAg positive) based on serology assessment. Screening for chronic conditions is not required;
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of Osimertinib or Gefitinib;
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) \>470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead
• AstraZeneca: collaborator

Study Sites (23)

Institut Jules Bordet

Brussels, Bruxelles Région, 1070, Belgium

Location

Institut Bergonie

Bordeaux, France

Location

CHU de Brest

Brest, France

Location

Centre Francois Baclesse

Caen, France

Location

Centre Hopitalier Intercommunal De Creteil

Créteil, France

Location

Assistance Publique - Hopitaux de Marseille - Hopital Nord

Marseille, France

Location

Institut Paoli-Calmettes

Marseille, France

Location

Centre Paul Strauss

Strasbourg, France

Location

CHU Toulouse - Hopital Larrey

Toulouse, France

Location

Institut de Cancerologie de Lorraine

Vandœuvre-lès-Nancy, France

Location

Gustave Roussy

Villejuif, France

Location

King Hussein Cancer Center

Amman, Jordan

Location

Medical University of Gdansk

Gdansk, Poland

Location

University Clinic Golnik

Golnik, Slovenia

Location

The Institute Of Oncology

Ljubljana, Slovenia

Location

University Hospital A Coruna-Hospital Teresa Herrera

A Coruña, Spain

Location

Hospital Clinic Universitari de Barcelona

Barcelona, Spain

Location

Hospital De La Santa Creu I Sant Pau

Barcelona, Spain

Location

Vall d'Hebron Institut d'Oncologia

Barcelona, Spain

Location

Hospital Universitario 12 De Octubre

Madrid, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Spain

Location

Institut Catala d'Oncologia - ICO Badalona - Hospital De Mataro

Mataró, Spain

Location

Virgen del Rocio University Hospital

Seville, Spain

Location

Related Publications (1)

• Remon J, Besse B, Aix SP, Callejo A, Al-Rabi K, Bernabe R, Greillier L, Majem M, Reguart N, Monnet I, Cousin S, Garrido P, Robinet G, Campelo RG, Madroszyk A, Mazieres J, Curcio H, Wasag B, Pretzenbacher Y, Grillet F, Dingemans AC, Dziadziuszko R. 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 Apr 20;42(12):1350-1356. doi: 10.1200/JCO.23.01521. Epub 2024 Feb 7.

  PMID: 38324744 DERIVED

MeSH Terms

Interventions

osimertinib; Gefitinib

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Yassin Pretzenbacher
• Organization: EORTC

yassin.pretzenbacher@eortc.org

+32 2 774 1365

Study Officials

• Rafal Dziadziuszko, MD PhD

  Mecical University of Gdansk, Poland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2016
• First Posted: August 5, 2016
• Study Start: October 10, 2017
• Primary Completion: September 20, 2022
• Study Completion (Estimated): December 1, 2027
• Last Updated: October 31, 2025
• Results First Posted: October 31, 2025

Record last verified: 2025-10

Locations

ES (8); SL (2); BE (1); FR (10); JO (1); PL (1)