Background <p>Lung cancer remains one of the leading causes of mortality globally. For patients with epidermal growth factor receptor (EGFR) -mutated lung adenocarcinoma who develop resistance to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs), subsequent treatments typically involve a regimen that includes pemetrexed and platinum. However, the progression-free survival (PFS) achieved with this approach is limited to 4–5 months. There is an urgent need for effective and safe adjuvant therapies. Preliminary research suggests that Chinese herbal medicine (CHM) granules may extend PFS and improve quality of life (QoL), potentially offering a therapeutic strategy for advanced non-small-cell lung cancer (NSCLC). A rigorous, randomized clinical trial is warranted to confirm these findings. The aim of this study is to evaluate the efficacy and safety of CHM granules in combination with chemotherapy for patients with EGFR-mutated advanced lung adenocarcinoma following resistance to first-line EGFR-TKIs.</p> Method/design <p>This study is a multicenter, double-blind, randomized, placebo-controlled clinical trial in China. A total of 244 patients will be enrolled and randomly assigned to either the treatment group (chemotherapy plus CHM granules, <i>n</i> = 122) or the control group (chemotherapy plus placebo granules, <i>n</i> = 122). The primary outcome measure is PFS, with secondary outcomes including overall survival (OS), objective response rate (ORR), disease control rate (DCR), patient-reported quality of life assessed by the Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS), and Traditional Chinese Medicine (TCM) clinical syndrome scores. Adverse events will also be closely monitored.</p> Discussion <p>The study’s findings will provide an evidence-based evaluation of the combination of CHM granules with chemotherapy for treating EGFR-mutated advanced lung adenocarcinoma with resistance to first-line EGFR-TKIs. The results may inform the development of clinical guidelines for adjuvant therapy in this patient population.</p> Trial registration <p><a href="http://www.chictr.org.cn">http://www.chictr.org.cn</a>. Trial number: ChiCTR2000029144, Registered on 19 Aug, 2020.</p>