Pemetrexed plus platinum outperforms other platinum-based adjuvant chemotherapy regimens for resected stage II-IIIA lung adenocarcinoma: an open-label, historical-control study.

Background: Early-stage lung adenocarcinoma has the potential to achieve long-term survival through radical surgery and appropriate adjuvant therapy. Despite rapid advancements in perioperative treatment strategies, postoperative adjuvant chemotherapy remains critically valuable. However, the optimal adjuvant chemotherapy regimen is yet to be established. Therefore, we initiated this study to evaluate the efficacy and safety of pemetrexed (PEM) plus platinum versus other platinum-based regimes as postoperative adjuvant chemotherapy in patients with stage II-IIIA lung adenocarcinoma after radical surgery to provide further clinical practice evidence. Methods: We performed a non-randomized, open-label, historical-control study. Seventy-one patients with pathologic stage II-IIIA lung adenocarcinoma who had undergone complete resection were prospectively enrolled, all of whom received pemetrexed combined with platinum adjuvant chemotherapy every 3 weeks for 4 cycles. In addition, we retrospectively collected the data from 209 patients recorded between January 2003 and December 2021 with pathologic stage II-IIIA lung adenocarcinoma who received radical surgery followed by adjuvant non-PEM (paclitaxel, gemcitabine and vinorelbine) plus platinum as historical control. The primary end point was disease-free survival (DFS). Univariable and multivariable Cox proportional hazards regression analyses were performed to identify independent prognostic factors for DFS. Propensity score matching (PSM) was applied to generate best-matched pairs for the two categories. All adverse events (AEs) were collected and compared. Results: In the prospective group, the median follow-up was 45.6 months (interquartile range, 40.3-55.7 months). Thirty-five of the 71 prospective patients developed disease progression, and 2-year DFS was 67.61%. The median DFS was not reached in the PEM group, compared with 18.9 months [95% confidence interval (CI): 15.6-22.0] in the non-PEM group. In the overall unmatched population, Kaplan-Meier analysis demonstrated a significant improvement in DFS with PEM (median DFS not reached vs. 18.9 months; P<0.001, hazard ratio =0.499, 95% CI: 0.345-0.72). In the PSM-matched cohort, the DFS benefit with PEM remained statistically significant (P=0.01). Besides, AEs of all grades were reported more frequently in the non-PEM plus platinum group than in PEM based group, such as neutropenia (76.1% vs. 25.4%), anemia (48.3% vs. 8.5%) and thrombocytopenia (23.4% vs. 5.6%). Conclusions: This study showed that PEM plus platinum outperforms non-PEM plus platinum as an adjuvant chemotherapy regimen for resected stage II-IIIA lung adenocarcinoma and with better tolerability.