real-world experience with combination chemotherapy and osimertinib in poor prognostic group of metastatic egfr-mutated lung adenocarcinoma

Conditions: Lung Cancer (NSCLC)

Summary: 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

Eligibility criteria:
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 \ 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.

Keywords: osimertinib chemotherapy ctdna advance stage lung cancer