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

NCT ID: NCT02856893

Last Updated: 2025-10-31

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 156 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-10
• Study Completion Date: 2027-12-31

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.

Detailed Description

Primary objective To evaluate the best strategy for delivering Osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFSR-OSI-18).

Secondary objectives

• To evaluate PFS while receiving osimertinib measured from randomization by RECIST criteria 1.1.
• To evaluate PFS measured from switching to osimertinib by RECIST criteria 1.1.
• To determine the proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation positive.
• To evaluate PFS-2.
• To evaluate Overall Response Rate (ORR) to osimertinib.
• To evaluate the Treatment duration.
• To evaluate Time to progression (TTP) on osimertinib (measured from switching to osimertinib).
• To evaluate Overall Survival (OS).
• To evaluate brain progression free survival (BPFS).
• Safety.

Conditions

NSCLC

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Osimertinib till progression

Osimertinib until PD according to RECIST 1.1

Group Type: EXPERIMENTAL

Osimertinib

Intervention Type: DRUG

Osimertinib 60 or 40 mg daily until progression

Gefitinib till + blood test/progression than Osimertinib

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

Group Type: EXPERIMENTAL

Osimertinib

Intervention Type: DRUG

Osimertinib 60 or 40 mg daily until progression

Gefitinib

Intervention Type: DRUG

Gefitinib 250mg daily until progression

Gefitinib till progression than Osimertinib

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

Group Type: ACTIVE_COMPARATOR

Osimertinib

Intervention Type: DRUG

Osimertinib 60 or 40 mg daily until progression

Gefitinib

Intervention Type: DRUG

Gefitinib 250mg daily until progression

Interventions

Osimertinib

Osimertinib 60 or 40 mg daily until progression

Intervention Type: DRUG

Gefitinib

Gefitinib 250mg daily until progression

Intervention Type: DRUG

Other Intervention Names

AZD9291, Tagrisso; Iressa

Eligibility Criteria

Inclusion Criteria

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;
• Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and defined as follows:
• Absolute neutrophil count ≥1.5 x 109/L;
• Platelet count ≥100 x 109/L;
• Haemoglobin ≥9 g/dL;
• Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases;
• Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation);
• No significant comorbidity that according to the investigator would hamper the participation on the trial;
• Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.
• Male patients should be willing to use barrier contraception, i.e., condoms

o Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children, and not to donate sperm until 6 months after discontinuation of study treatment." (as per Investigator Brochure, IB)

• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion:

• 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
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec or history of episodes of bradycardia (<50 BPM);
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
• Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO)
• Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rafal Dziadziuszko, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Mecical University of Gdansk, Poland

Locations

Institut Jules Bordet

Brussels, Bruxelles Région, Belgium

Institut Bergonie

Bordeaux, , France

CHU de Brest

Brest, , France

Centre Francois Baclesse

Caen, , France

Centre Hopitalier Intercommunal De Creteil

Créteil, , France

Assistance Publique - Hopitaux de Marseille - Hopital Nord

Marseille, , France

Institut Paoli-Calmettes

Marseille, , France

Centre Paul Strauss

Strasbourg, , France

CHU Toulouse - Hopital Larrey

Toulouse, , France

Institut de Cancerologie de Lorraine

Vandœuvre-lès-Nancy, , France

Gustave Roussy

Villejuif, , France

King Hussein Cancer Center

Amman, , Jordan

Medical University of Gdansk

Gdansk, , Poland

University Clinic Golnik

Golnik, , Slovenia

The Institute Of Oncology

Ljubljana, , Slovenia

University Hospital A Coruna-Hospital Teresa Herrera

A Coruña, , Spain

Hospital Clinic Universitari de Barcelona

Barcelona, , Spain

Hospital De La Santa Creu I Sant Pau

Barcelona, , Spain

Vall d'Hebron Institut d'Oncologia

Barcelona, , Spain

Hospital Universitario 12 De Octubre

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

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

Mataró, , Spain

Virgen del Rocio University Hospital

Seville, , Spain

Countries

Belgium; France; Jordan; Poland; Slovenia; Spain

References

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.

Reference Type: DERIVED

PMID: 38324744 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

ESR-15-11406

Identifier Type: OTHER

Identifier Source: secondary_id

EORTC-1613

Identifier Type: -

Identifier Source: org_study_id