Clinical trialPhase 3Lung cancer

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

N Engl J Med · 2023557 patients

Planchard D, Jänne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, et al. N Engl J Med. 2023. 389:1935-1948

A newer report of this study has been published: Survival with Osimertinib plus Chemotherapy in EGFR -Mutated Advanced NSCLC (2026)

Study type: Clinical trial
Study name: FLAURA2
Phase: Phase 3
Design: International randomised open-label trial (1:1)
Sample size: 557 patients
Source: N Engl J Med · 2023
Trial registration: NCT04035486

In plain words

For advanced lung cancer with an EGFR mutation, osimertinib tablets are the standard treatment. This study showed that adding chemotherapy (pemetrexed and a platinum drug) to osimertinib keeps the disease under control for longer and, in the final analysis, increased how long patients lived on average by about 10 months; but it has more side effects and needs regular infusions. The choice between these two approaches depends on your situation and preferences.

Key results

HR 0.62

Progression-free survival (investigator assessment)

95% CI 0.49 to 0.79; P<0.001

25.5 months vs 16.7 months

Median progression-free survival (investigator assessment; FDA label)

95% CI 24.7 to not estimable vs 14.1 to 21.3; HR 0.62 (0.49 to 0.79)

57% vs 41%

Alive and progression-free at 24 months

HR 0.62

PFS by blinded independent central review

95% CI 0.48 to 0.80

83% vs 76%

Objective response

Median duration of response 24.0 vs 15.3 months

47.5 vs 37.6 months

Median overall survival (final analysis, separate paper)

HR 0.77; 95% CI 0.61 to 0.96; P=0.02 — Jänne PA et al., N Engl J Med 2026; DOI: 10.1056/NEJMoa2510308

Drugs in this study:Carboplatin (Paraplatin)Cisplatin (Platinol)Osimertinib (Tagrisso)

Dose and schedule cards

Osimertinib + pemetrexed + platinum (FLAURA2)

Locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R; first-lineEach drug’s schedule in the tableOn the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R; first-line

Drug	Dose	Route	Schedule
Induction: 4 cycles of 21 days
Osimertinib	80 mg	Oral	Once daily, continuous
Pemetrexed	500 mg/m²	IV (10 min)	Day 1, every 21 days
Cisplatin or carboplatin	75 mg/m² or AUC 5	IV	Day 1, every 21 days
Maintenance
Osimertinib	80 mg	Oral	Once daily
Pemetrexed	500 mg/m²	IV	Every 3 weeks

Cycle schedule: Pemetrexed (and platinum during the 4 induction cycles) every 21 days; osimertinib daily and continuously
Duration: 4 induction cycles, then maintenance until progression or intolerable toxicity

Source: FDA label for osimertinib (description of the FLAURA2 trial); overall survival. With this combination, assess LVEF before starting in all patients; interstitial lung disease occurred in 3.3%.

On the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Osimertinib + pemetrexed + platinum (FLAURA2)

Locally advanced or metastatic NSCLC, first line, exon 19 deletion or L858ROn the page “Osimertinib (Tagrisso)” · Standard dosing (FDA label)

Locally advanced or metastatic NSCLC, first line, exon 19 deletion or L858R

Drug	Dose	Route	Schedule
Osimertinib	80 mg	Oral	Once daily, continuously
Pemetrexed + cisplatin or carboplatin	As per each drug's label	IV	As per each drug's label

Cycle length: Osimertinib daily; chemotherapy as per those drugs' labels
Duration: Until disease progression or unacceptable toxicity from osimertinib

The osimertinib label does not specify pemetrexed and platinum doses and refers to those drugs' labels. For toxicity, each drug's dose is modified separately. LVEF assessment is needed in all patients before starting.

On the page “Osimertinib (Tagrisso)” · Standard dosing (FDA label)

Osimertinib + chemotherapy

Advanced EGFR-positive lung cancer, first lineEach drug’s schedule in the tableOn the page “Osimertinib with pemetrexed and platinum (FLAURA2)”

Advanced EGFR-positive lung cancer, first line

Drug	Dose	Route	Schedule
Phase 1: 4 cycles
Osimertinib	80 mg	Oral	Daily
Pemetrexed	500 mg/m²	IV	Day 1
Cisplatin 75 mg/m² or carboplatin (Calvert-based dose)		IV	Day 1
Phase 2
Osimertinib	80 mg	Oral	Daily
Pemetrexed	500 mg/m²	IV	Every 3 weeks

Cycle schedule: Chemotherapy every 21 days; osimertinib daily
Duration: Until progression

As in FLAURA2; dose source:.

On the page “Osimertinib with pemetrexed and platinum (FLAURA2)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Osimertinib + pemetrexed and platinum

Induction (4 cycles): osimertinib 80 mg orally once daily, with pemetrexed 500 mg/m² and, at the investigator's choice, cisplatin 75 mg/m² or carboplatin AUC 5, all IV on day 1 of 21-day cycles (every 3 weeks).

Maintenance: osimertinib 80 mg daily with pemetrexed 500 mg/m² IV every 3 weeks, until intolerance or for as long as clinical benefit continued in the investigator's opinion. (279 patients)

Dose reduction was allowed to manage adverse events. According to the FDA label, in combination therapy each drug's dose is modified separately: osimertinib according to its own dose-modification table (80 → 40 mg), and pemetrexed, cisplatin or carboplatin according to their respective labels. Inclusion criterion: creatinine clearance of 60 mL/min or more.

2Osimertinib monotherapy

Osimertinib 80 mg orally once daily until intolerance or loss of clinical benefit; dose reduction was allowed to manage adverse events. (278 patients)

Source of the regimen details: ClinicalTrials.gov NCT04035486 (arms, doses, 4 induction cycles and pemetrexed maintenance) and the FDA label for Tagrisso (DailyMed, 2026 version); the full text was not available in PMC

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with newly diagnosed non-squamous NSCLC (mixed histology allowed), locally advanced (stage IIIB or IIIC), metastatic (IVA or IVB) or recurrent, not amenable to curative surgery or radiotherapy; with an EGFR exon 19 deletion or L858R (alone or with other EGFR mutations including T790M); no prior treatment for advanced disease; WHO performance status 0 to 1; measurable disease (RECIST 1.1). Stable brain metastases after definitive treatment without steroids, and asymptomatic brain metastases not needing immediate treatment in the investigator's opinion, were allowed.

Key exclusion criteria: history of ILD or radiation pneumonitis requiring steroids, QT prolongation or significant rhythm disturbance, neutrophils or platelets below the lower limit of normal, haemoglobin below 90 g/L (without using G-CSF or transfusion to meet the criterion), ALT/AST above 2.5 times the upper limit (5 times with liver metastases), bilirubin above 1.5 times the upper limit, and creatinine clearance below 60 mL/min.

Endpoints

Primary endpoint: investigator-assessed progression-free survival (PFS). Key secondary: overall survival; also response, duration of response and safety.

Safety and side effects

In the primary paper, grade 3 or higher adverse events of any cause were more frequent with the combination than with monotherapy, owing to known chemotherapy toxicities. In the final overall survival analysis (2026 paper), grade 3 or higher adverse events were reported in 70% of the combination group versus 34% of the monotherapy group, and osimertinib discontinuation because of adverse events was 12% versus 7%.

According to the FDA label (FLAURA2 combination group, 276 patients; median exposure 22.3 months): serious adverse events 38% (most common: anaemia 3.3%, pneumonia 2.5%, febrile neutropenia 2.2%, thrombocytopenia 2.2% and pulmonary embolism 2.2%); fatal adverse events 7% (including pulmonary embolism 1.1%, pneumonia 1.1% and cardiomyopathy 1.1%); ILD/pneumonitis 3.3% (0.4% fatal); cardiomyopathy 9% and LVEF decline of 10 percentage points or more to below 50% in 8%; QTc above 500 ms 1.8%. Osimertinib interruption 44%, dose reduction 10% and permanent discontinuation 11% (mainly ILD/pneumonitis 2.9%, pneumonia 1.4% and decreased ejection fraction 1.1%). The most common adverse events were leucopenia, thrombocytopenia, neutropenia, rash, diarrhoea, stomatitis, nail toxicity, dry skin and increased blood creatinine.

Clinical significance and place in guidelines

FLAURA2 made osimertinib plus pemetrexed–platinum one of the first-line options for advanced EGFR-mutated NSCLC (FDA approval in February 2024). With the publication of the overall survival benefit (HR 0.77) in 2026, this regimen, alongside amivantamab–lazertinib (MARIPOSA), is one of the two intensified strategies with a proven overall survival benefit; osimertinib monotherapy remains a valid option, particularly for lower-risk patients or those unable to tolerate chemotherapy.

Limitations

The design was open-label; grade 3 or higher adverse events roughly doubled with the combination; criteria for selecting patients who benefit most (for example, brain metastases, L858R mutation or co-occurring TP53 mutations) are still under study, and there is no direct comparison with amivantamab–lazertinib.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.