Abstract
BACKGROUND: A standard first-line regimen for patients with driver-gene-negative metastatic non-squamous non-small cell lung cancer (nsqNSCLC) is immune checkpoint inhibitors (ICIs) combined with pemetrexed and platinum, followed by maintenance therapy. However, the role of long-term pemetrexed maintenance remains controversial. This study evaluated the impact of pemetrexed maintenance discontinuation. METHODS: A total of 167 patients diagnosed with driver-gene-negative metastatic nsqNSCLC were treated with first-line ICIs plus pemetrexed and platinum as induction therapy between September 2020 and April 2024 at the Department of Medical Oncology, Fudan University Shanghai Cancer Center. The primary endpoint was progression-free survival (PFS). Patients who permanently discontinued pemetrexed at any time during maintenance for any reason were categorized as the ICIs maintenance group, while those who continued pemetrexed were categorized as the ICIs + pemetrexed maintenance group. RESULTS: Of the 167 patients, 141 received maintenance therapy, including 101 with ICIs plus pemetrexed maintenance, and 40 with ICIs maintenance. The median PFS was 26.9 months for ICIs maintenance group and 12.4 months for ICIs + pemetrexed maintenance group (P=0.052). No significant difference was observed in median PFS between ICIs and ICIs + pemetrexed maintenance group after propensity score matching. Biomarker analysis showed that in ICIs maintenance group, patients experiencing Grade 2 or higher lymphopenia before or during treatment and patients with low baseline plasma extracellular vesicle-derived EHF gene expression showed significantly prolonged survival. CONCLUSIONS: This study demonstrated that discontinuation of pemetrexed maintenance did not compromise the efficacy of the first-line immunochemotherapy of metastatic driver-gene-negative nsqNSCLC, and identified potential biomarkers for decision making of pemetrexed discontinuation.