A Study to Evaluate Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC)

A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Platinum Plus Pemetrexed Chemotherapy Plus Osimertinib Versus Platinum Plus Pemetrexed Chemotherapy Plus Placebo in Patients With EGFRm, Locally Advanced or Metastatic NSCLC Who Have Progressed Extracranially Following First-Line Osimertinib Therapy (COMPEL)

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04765059

Acronym

COMPEL

Enrollment

Registered

2021-02-21

Start date

2021-09-12

Completion date

2027-06-02

Last updated

2026-07-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Non-small Cell Lung Cancer

Keywords

Osimertinib, Platinum, Pemetrexed, Epidermal growth factor receptor mutation positive (EGFRm), Extracranial progression

Brief summary

The study will evaluate the efficacy and safety of treatment with chemotherapy in combination with osimertinib compared to chemotherapy in combination with placebo in patients whose disease has progressed extracranially following first-line osimertinib treatment.

Detailed description

This is a Phase III, randomized, double-blind, placebo-controlled study of platinum plus pemetrexed chemotherapy plus osimertinib versus platinum plus pemetrexed chemotherapy plus placebo in patients with epidermal growth factor receptor mutation-positive (EGFRm), locally advanced or metastatic NSCLC with or wihout stable brain metastases who responded to first-line osimertinib therapy (complete response \[CR\] or partial response \[PR\]) or stable disease (SD) for ≥ 6 months during first-line osimertinib treatment, and subsequently experienced radiological, extracranial disease progression. Approximately 204 patients were to be randomized in a 1:1 ratio to treatment with platinum plus pemetrexed chemotherapy plus osimertinib (Treatment Arm A) or platinum plus pemetrexed chemotherapy plus placebo (Treatment Arm B). However, the number of patients has been reduced to approximately 80 patients due to treatment landscape changes which outpaced study recruitment. Patients will be stratified based on the presence of brain metastases (stable brain metastases based on central nervous system (CNS) Response Evaluation Criteria in Solid Tumors, Version 1.1 \[RECIST 1.1\] assessments versus no brain metastases). The 2 randomized treatment regimens are as follows: * Treatment Arm A: Osimertinib 80 mg once daily (QD) with pemetrexed (500 mg/m\^2) (with pre-treatment) plus either cisplatin (75 mg/m\^2) or carboplatin (area under the concentration-time curve \[AUC\] 5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance (500 mg/m\^2) on Day 1 of 21-day cycles * Treatment Arm B: Placebo QD with pemetrexed (500 mg/m\^2) (with pre-treatment) plus either cisplatin (75 mg/m\^2) or carboplatin (AUC5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by placebo QD plus pemetrexed maintenance (500 mg/m\^2) on Day 1 of 21-day cycles.

Interventions

DRUGOsimertinib (AZD9291) pemetrexed cisplatin or carboplatin

Randomized patients will receive oral dose of osimertinib with intravenous (IV) pemetrexed plus either IV cisplatin or IV carboplatin

DRUGPlacebo for osimertinib (AZD9291) pemetrexed cisplatin or carboplatin

Randomized patients will receive oral dose of placebo matching osimertinib with IV pemetrexed plus either IV cisplatin or IV carboplatin

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

The patient, the Investigator, the study team (Sponsor, Contract research organization) and the study site staff will be blinded to osimertinib or placebo allocation. Patients may participate in the open label part of trial at the discretion of the investigator to receive osimertinib and continue any ongoing chemotherapy if intracranial progression is their first progression event.

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

Inclusion criteria

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol. 2. Pathologically confirmed non-squamous NSCLC. 3. Locally advanced (clinical stage IIIB or IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC, not amenable to curative surgery or radiotherapy. 4. Evidence of radiological extracranial disease progression following (Investigator-assessed) response or SD for ≥ 6 months during first-line osimertinib treatment, but who have not received further, subsequent treatment. 5. Tumor known to harbor 1 of the 2 or both common epidermal growth factor receptor (EGFR) mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M. 6. World Health Organization performance status of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks. 7. Life expectancy \>12 weeks at Day 1. 8. At least 1 lesion, not previously irradiated, that can be accurately measured. 9. Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling criteria at screening. 10. Male patients must be willing to use barrier contraception

Exclusion criteria

1. Clinical or radiological evidence of CNS progression on first-line osimertinib. 2. Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-induced ILD/pneumonitis, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD/pneumonitis. 3. Any evidence of severe or uncontrolled systemic diseases. 4. Any of the following cardiac criteria: i) Mean resting QTc \>470 msec ii) Any clinically important abnormalities in rhythm, conduction, or morphology of resting electrocardiogram iii) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 5. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of investigational product (IP). 6. Any unresolved toxicities from prior therapy. 7. 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. 8. More than 4 weeks elapsed since last dose of osimertinib by date of randomization. 9. Unable to tolerate osimertinib 80 mg first-line therapy. 10. Prior treatment with any systemic anti-cancer therapy. 11. Major surgery within 4 weeks of the first dose of IP. 12. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. 13. Current use of medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4. 14. Participation in another clinical study with an IP other than first-line osimertinib during the 4 weeks prior to Day 1.

Design outcomes

Primary

Measure	Time frame	Description
Progression Free Survival (PFS)	From date of first dose (Day 1) until date of progression at local site or death due to any cause or data cut-off date whichever occurred first (up to 3 years 1 month)	Progression free survival is defined as time from randomization until progression (intracranial or extracranial, whichever occurs first) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for extracranial progression) and Central nervous system (CNS) RECIST 1.1 (for intracranial progression) as assessed by the Investigator at local site or death due to any cause.

Secondary

Measure	Time frame	Description
Intracranial Progression Free Survival in Participants With Brain Metastases at Baseline	Assessed from date of first dose (Day 1) until date of intracranial progression at local site or death due to any cause or data cut off date whichever occurred first (up to 3 years 1 month), data for 6 months reported	Intracranial PFS (IC-PFS) is defined as time from randomization until intracranial progression per CNS RECIST 1.1 as assessed by the Investigator at local site or death due to any cause. For participants with brain metastases at baseline, the IC-PFS rate at specified timepoints was estimated using the Kaplan-Meier method which indicated the percentage of these participants who remain alive and free from intracranial progression per CNS RECIST 1.1 as assessed by the Investigator. The data was calculated throughout the study as per the below timeframe but IC-PFS rate at 6 months has been presented as it was clinically relevant.
Intracranial Progression Free Survival in Participants Without Brain Metastases at Baseline	Assessed from date of first dose (Day 1) until date of intracranial progression at local site or death due to any cause or data cut off date whichever occurred first (up to 3 years 1 month), data for 6 months reported	Intracranial PFS (IC-PFS) is defined as time from randomization until intracranial progression per CNS RECIST 1.1 as assessed by the Investigator at local site or death due to any cause. For participants without brain metastases at baseline, the IC-PFS rate at specified timepoints was estimated using the Kaplan-Meier method which indicated the percentage of these participants who remain alive and free from intracranial progression per CNS RECIST 1.1 as assessed by the Investigator. The data was calculated throughout the study as per the below timeframe but IC-PFS rate at 6 months has been presented as it was clinically relevant.
Extracranial Progression Free-survival	From date of first dose (Day 1) until date of extracranial progression at local site or death due to any cause or data cut-off date whichever occurred first (up to 3 years 1 month)	Extracranial PFS is defined as time from randomization until extracranial progression per RECIST 1.1 as assessed by the Investigator at local site or death due to any cause.
Overall Survival (OS)	From date of first dose (Day 1) until post progression survival follow-up (up to 3 years 1 month)	Overall survival is defined as the length of time from randomization until the date of death due to any cause.

Countries

China, Germany, Israel, Italy, Spain, United States

Participant flow

Recruitment details

Participants were enrolled in this study from 12 September 2021 (First participant in) and the analyses presented in this results form are based on a final data cut-off of 28 October 2024.

Pre-assignment details

Participants meeting eligibility criteria predefined in protocol were enrolled in the study. Assessments performed as per the schedule of the assessments.

Participants by arm

Arm	Count
Treatment Arm A: Osimertinib (AZD9291), Pemetrexed, Cisplatin or Carboplatin Participants received osimertinib 80 mg once daily (QD) with pemetrexed (500 mg/m2) (with pre-treatment) plus either cisplatin (75 mg/m2) or carboplatin, both administered on Day 1 of 21-day cycles for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance (500 mg/m2) on Day 1 of 21-day cycles.	49
Treatment Arm B: Placebo for Osimertinib (AZD9291), Pemetrexed, Cisplatin or Carboplatin Participants received placebo QD with pemetrexed (500 mg/m2) (with pre-treatment) plus either cisplatin (75 mg/m2) or carboplatin, both administered on Day 1 of 21-day cycles for 4 cycles, followed by placebo QD plus pemetrexed maintenance (500 mg/m2) on Day 1 of 21-day cycles.	49
Total	98

Baseline characteristics

Characteristic	Treatment Arm A: Osimertinib (AZD9291), Pemetrexed, Cisplatin or Carboplatin	Treatment Arm B: Placebo for Osimertinib (AZD9291), Pemetrexed, Cisplatin or Carboplatin	Total
Age, Continuous	62.0 Years STANDARD_DEVIATION 11.39	61.0 Years STANDARD_DEVIATION 10.02	61.5 Years STANDARD_DEVIATION 10.68
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	7 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	45 Participants	42 Participants	87 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	30 Participants	39 Participants	69 Participants
Sex: Female, Male Male	19 Participants	10 Participants	29 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	26 / 48	28 / 48
other Total, other adverse events	46 / 48	47 / 48
serious Total, serious adverse events	18 / 48	15 / 48

Outcome results

Primary

Progression Free Survival (PFS)

Progression free survival is defined as time from randomization until progression (intracranial or extracranial, whichever occurs first) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for extracranial progression) and Central nervous system (CNS) RECIST 1.1 (for intracranial progression) as assessed by the Investigator at local site or death due to any cause.

Time frame: From date of first dose (Day 1) until date of progression at local site or death due to any cause or data cut-off date whichever occurred first (up to 3 years 1 month)