Nedaplatin plus pemetrexed or cisplatin plus pemetrexed as first-line chemotherapy for EGFR/ALK-negative advanced lung adenocarcinoma (NACA): A multicenter, open-label, non-inferiority, randomized, phase III trial.

9089 Background: Platinum-based chemotherapy is the backbone of treatment for advanced non-small cell lung cancer. Cisplatin has well-known side effects such as gastrointestinal reaction and fatigue, and nedaplatin was developed to be an alternative platinum with less toxicity. We aimed to compare nedaplatin plus pemetrexed was non-inferior to cisplatin plus pemetrexed as first-line chemotherapy for advanced EGFR/ALK-negative lung adenocarcinoma. Methods: We did an open-label, randomized, phase III trial at 15 centers in China. Advanced lung adenocarcinoma patients with EGFR/ALK-negative status were randomly assigned to receive nedaplatin 90 mg/m2 or cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 for 6 cycles as first-line treatment, and pemetrexed maintenance for those without progressive disease. The primary endpoint was progression-free survival (PFS), non-inferiority was shown if the upper limit of the 95% CI for the hazard ratio (HR) of PFS did not exceed 1.30. Secondary endpoints included objective response, overall survival and toxicity. This trial is registered with ClinicalTrials.gov, number NCT02607592. Results: Between Sep 2015 and May 2021, 218 patients were randomized to nedaplatin group (n = 111) or cisplatin group (n = 107). In the intention-to-treat population, median PFS time was 6.87 months (95%CI, 5.25 to 8.49) in the nedaplatin group and 5.53 months (95%CI, 4.57 to 6.50) in the cisplatin group, with a HR of 0.76 (95%CI, 0.56 to 1.03, p= 0.078). In the per-protocol population (nedaplatin group, n = 105; cisplatin group, n = 94), median PFS time was 6.87 months (95%CI, 5.36 to 8.37) and 5.20 months (95%CI, 4.03 to 6.37) respectively, with a HR of 0.76 (95%CI, 0.56 to 1.03, p= 0.082). Overall response rate was 41.9% in nedaplatin group and 26.6% in cisplatin group ( p= 0.026). A significantly higher frequency of any grade nausea and vomiting (51[53.68%] of 95 in the cisplatin group vs 30[28.04%] of 107 in the nedaplatin group, p< 0.001), fatigue (37[38.95%] vs 27[25.23%], p= 0.037), and constipation (15[15.79%] vs 5[4.67%], p= 0.008) were reported in the cisplatin group compared with the nedaplatin group. Higher rate of grade 3/4 nausea and vomiting was observed in cisplatin group (10[10.53%] vs 0, p= 0.001). Patients in the nedaplatin group had higher frequency of thrombocytopenia but without statistical significance (any grade: 28[26.17%] of 107 in the nedaplatin group vs17[17.89%] of 95 in the cisplatin group, p= 0.158; grade 3/4: 8[7.48%] in the nedaplatin group vs 3[3.16%] in the cisplatin group, p= 0.177). Conclusions: Our findings show that nedaplatin plus pemetrexed is not inferior to cisplatin plus pemetrexed in progression-free survival, with less toxicities, which represents an alternative chemotherapy regimen for EGFR/ALK-negative advanced lung adenocarcinoma. Clinical trial information: NCT02607592.