The aims of this study are to determine the potential clinical benefits (in terms of PFS, objective response and OS) of add-on systemic chemotherapy (pemetrexed+carboplatin/cisplatin) to first-line osimertinib treatment among the poor prognostic group of metastatic EGFR-mutant lung adenocarcinoma, i.e. failure of plasma ctDNA EGFR mutant clearance at week 3 after osimertinib treatment

This is a single-arm clinical trial, subjects will be consented prior to the initiation of osimertinib (as per standard-of-care) with baseline plasma ctDNA EGFR mutations tested in QMH. Those with detectable baseline plasma ctDNA EGFR mutations will undergo a repeat plasma ctDNA test after 3 weeks (+/- 5 days) of osimertinib treatment. The screening period is within 42 days. Enrolled eligible subjects will be started on systemic chemotherapy (pemetrexed and carboplatin or cisplatin) within 6 weeks of starting osimertinib, with the following outcome measures:

Primary outcome: real-world 1-year progression-free survival (rw1yPFS) Secondary outcomes: rw response rate (rwRR), rw PFS (rwPFS), rw overall survival (rwOS), rw time-to-treatment discontinuation (rwTTD), ctDNA clearance rate

Inclusion Criteria:

1. Adults above 18 years old, both male and female;
2. Pathologically confirmed lung adenocarcinoma with stage IIIB/C or IV disease (TNM staging version 8);
3. Confirmed EGFR common sensitizing mutations (exon 21 L858R or exon 19 del) by locally approved molecular testing methods (allele-specific PCR or NGS) based on tumour tissues or plasma ctDNA;
4. Clinically decided for first-line systemic treatment with osimertinib;
5. Detectable pre-treatment plasma EGFR mutations (by Cobas EGFR Mutation Test v2) and failed clearance 3 weeks (+/- 5 days) after osimertinib treatment;
6. At least one measurable target lesion by RECIST v1.1 criteria;
7. Performance state (ECOG) ≤ 1 and life expectancy ≥ 12 weeks;
8. Females in reproductive age with negative pregnancy test and highly effective means of contraception during and ≥ 4 months after intervention period;
9. Males should agree to have highly effective means of contraception during and ≥ 4 months after intervention period; and
10. Written informed consent obtained.

Exclusion Criteria:

1. Mixed NSCLC and small cell carcinoma;
2. Prior systemic anticancer treatment (targeted therapy, chemotherapy or immunotherapy) for metastatic stage NSCLC;
3. Prior adjuvant chemotherapy or targeted therapy within 6 months;
4. Local radiotherapy within 2 weeks or major surgery within 4 weeks;
5. Inadequate haematological function (haemoglobin < 9 g/dL, neutrophils < 1.5 x 109/L, platelets < 100 x 109/L), renal function (serum creatinine ≥ 1.5 x upper limit of normal (ULN) or creatinine clearance < 45 ml/min) or liver function (total bilirubin > 1.5 x ULN, ALT/AST/ALP > 3 x ULN; ALT/AST/ALP > 5 x ULN for liver metastases; ALP > 5 x ULN for bone metastases);
6. Major medical comorbidities with significant organ dysfunction;
7. Known active hepatitis B or C infection. Chronic hepatitis B on antiviral allowed as per institutional guideline for chemotherapy;
8. Malignancies other than NSCLC; and
9. Known hypersensitivity to pemetrexed or carboplatin.