Osimertinib plus chemotherapy as 1st line therapy in stage IV NSCLC patients with atypical EGFR mutations (AIO-TRK/YMO-0324)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitat Heidelberg

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

4 Sep 2025 → ongoing

Decision date (initial)

2025-03-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the efficacy of osimertinib along with chemotherapy in stage IV NSCLC patients with atypical EGFR mutations (EGFR mutations in Exons 18-21 excluding L858R, Exon 19 del, Exon 20 Ins or T790M mutation).

Secondary objectives 1

1. To evaluate the efficacy as well as to assess the safety and the impact on the quality of life of the patients of osimertinib along with chemotherapy in stage IV NSCLC patients with atypical EGFR mutations

Conditions and MedDRA coding

stage IV NSCLC (non-small-cell lung cancer)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patient has provided written informed consent
2. Patient is 18 years or older at time of signing the informed consent form
3. Patient has histologically or cytologically confirmed stage IV NSCLC (adenocarcinoma)
4. Patient did not receive prior systemic treatment for metastatic stage
5. Patient has one or more EGFR mutations in Exons 18-21 excluding L858R, Exon 19 del, Exon 20 Ins or T790M mutation (tested locally)
6. Patient has negative molecular testing for ALK and ROS1 alterations (tested locally)
7. Patient has ECOG performance status ≤ 1
8. Patient must have a life expectancy ≥ 12 weeks
9. Patient has at least one measurable lesion according to RECIST v1.1
10. 10. Patient has adequate hepatic, renal and bone marrow function: a) Hemoglobin ≥ 9.0 g/dL b) Absolute neutrophil count ≥ 1.5 x 109 /L c) Platelets ≥ 100 x 109 /L d) Calculated creatinine clearance ≥ 60 mL/min (use of CKD-EPI formulation is highly recommended) and creatinine ≤ 1.5x upper limit of normal (ULN) e) Serum bilirubin ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of documented Gilbert‘s Syndrome [unconjugated hyperbilirubinemia] or liver metastases) f) AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN (or ≤5 times ULN in the presence of liver metastases) g) International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants
11. Female patients who are considered as woman of childbearing potential (WOCBP) must agree to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of <1% per year during the treatment period as well as up to 2 months after last dose of osimertinib or 6 months after last dose chemotherapy, whatever is later (see section 5.2.6).
12. WOCBP must have a negative serum pregnancy test and not be breast-feeding prior to start of the trial treatment
13. Male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive during the treatment period as well as up to 4 months after last dose of osimertinib, 3 months after last dose of pemetrexed or up to 6 months after last dose of carboplatin or cisplatin, whatever is later. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy (see section 5.2.6).

Exclusion criteria 16

1. Mixed histology (small-cell and non-small cell or non-squamous and squamous; patients exhibiting the latter expression pattern may be eligible if the adenocarcinoma part predominates in >50% of analyzed tumor tissue)
2. Patients having received any prior therapy with an EGFR TKI
3. Patient is candidate for complete removal of oligometastatic disease. If patients refuse to undergo surgery/ablations they are allowed into the trial
4. Patient received treatment with an investigational drug within five half-lives of the compound or 3 months before start of the trial treatment, whichever is greater
5. Patient is currently receiving (or unable to stop prior start of the trial treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior) (see Appendix 3). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
6. Patient has symptomatic, neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to trial entry (maximal acceptable dose must be ≤ 10 mg of prednisolone)
7. Patient has any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of start of trial treatment, with exception of alopecia and grade 2 prior platinum-therapy-related neuropathy
8. Patient has 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
9. Patient has known active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HCV/ HIV), or active uncontrolled HBV infection. Screening for chronic conditions is not required. Patients with chronic/ resolved HBV are eligible if they meet the following criteria: • Negative for hepatitis B surface antibody (HBsAb) and positive for hepatitis B core antibody (HBcAb). In addition, patients must be receiving anti-viral prophylaxis for 2- 4 weeks prior to study treatment OR • Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV DNA levels below <100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment
10. Patient has refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow tablets or previous significant bowl resection that would preclude adequate absorption of osimertinib
11. Patient has any of the following cardiac criteria: • Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN) , 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 and cause Torsades de Pointes
12. Leptomeningeal disease
13. Patient has past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
14. Known additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 years
15. Known allergy or hypersensitivity to any component of the chemotherapy regimen or to osimertinib or any constituents of the products
16. Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival rate at 12 months (PFS@12) according to RECIST 1.1, defined as the proportion of patients alive with non-progressive disease 12 months after enrollment and estimated by the Kaplan-Meier method.

Secondary endpoints 5

1. Progression-free survival rate (PFS), defined as time from enrollment to the date of progression according to RECIST 1.1 or death due to any cause
2. Overall survival (OS), defined as time from enrollment to the date of death due to any cause
3. Objective response rate (ORR), defined as rate of patients achieving complete response (CR) or partial response (PR) according to RECIST 1.1 as best overall response
4. Toxicity according to CTCAE 5.0
5. Progression-free survival rate (PFS2) as defined by time from initial trial randomization to second disease progression or death from any cause

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitat Heidelberg

Sponsor organisation

Universitat Heidelberg

Address

Seminarstrasse 2, Altstadt Altstadt

City

Heidelberg

Postcode

69117

Country

Germany

Scientific contact point

Organisation

Universitat Heidelberg

Contact name

Dr. Maike Collienne

Public contact point

Organisation

Universitat Heidelberg

Contact name

Dr. Maike Collienne

Third parties 2

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications