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All randomized patients will receive osimertinib 80 mg QD with pemetrexed (500 mg/m\^2) (with pre-treatment) plus either cisplatin (75 mg/m\^2) or carboplatin (\[AUC\] 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

All randomized patients will receive 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

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

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

Placebo for osimertinib (AZD9291) pemetrexed cisplatin or carboplatin

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.

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.

The patient, the Investigator, 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.

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)

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on PFS

To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on intracranial PFS in patients with baseline brain metastases and patients without baseline brain metastases

To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on extracranial PFS

To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on OS

To assess the safety and tolerability of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo in patients with locally advanced or metastatic EGFRm NSCLC whose disease has progressed extracranially on first-line osimertinib treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Evaluate Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC)	NCT04765059	Non-small Cell ...	Osimertinib (AZ... Placebo for osi...	18 Years - 130 Years	AstraZeneca
A Study to Evaluate Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC)	NCT04765059	Non-small Cell ...	Osimertinib (AZ... Placebo for osi...	18 Years - 130 Years	AstraZeneca

Spots Global Cancer Trial Database for extracranial progression