Maintenance therapy for metastatic non-squamous non-small cell lung cancer: lymphopenia as a biomarker for pemetrexed cessation

Abstract Background A standard first-line regimen for patients with metastatic non-squamous non-small cell lung cancer (nsqNSCLC) without driver gene mutations 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 discontinuation during maintenance therapy to prognosis. Patients and Methods Totally 167 patients diagnosed with metastatic nsqNSCLC without driver gene mutations were treated with first-line ICIs plus pemetrexed and platinum as induction therapy between September 2020 and April 2024 at our department. The primary endpoint was progression-free survival (PFS). Patients who 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. 101 out of 141 received ICIs plus pemetrexed maintenance, and 40 patients discontinued pemetrexed during maintenance. The median PFS was 26.9 months for ICIs maintenance group and 12.43 months for ICIs + pemetrexed maintenance group (p = 0.052). Patients under 65 years old, with smoking history, with bone metastasis, and most notably with Grade 2 or higher lymphopenia before or during treatment showed significantly longer PFS with ICIs maintenance compared to ICIs + pemetrexed maintenance. Conclusion This study demonstrated that discontinuation of pemetrexed maintenance did not impact the efficacy of the first-line immunochemotherapy of metastatic driver-gene negative nsqNSCLC, and proposed lymphopenia as a biomarker for the decision of pemetrexed discontinuation during maintenance.