Improved PFS and OS for switch maintenance with ramucirumab plus paclitaxel compared to continuation of chemotherapy in advanced HER2-negative gastric or GEJ cancer: results of phase III ARMANI trial

Despite standard first-line chemotherapy with platinum/fluoropyrimidine regimens for patients with gastric or gastroesophageal junction (GEJ) cancer, survival remains poor, especially in HER2-negative advanced cases. First-line chemotherapy is typically continued until disease progression or unacceptable toxicity, but the optimal duration is unknown. Switch consolidation maintenance or early second-line therapy may extend the benefits of initial treatment and delay clinical deterioration. The ARMANI study was designed to evaluate whether switch maintenance with ramucirumab plus paclitaxel could improve survival outcomes for patients with HER2-negative advanced gastric or GEJ cancer. The results were presented at ESMO-GI 2024.¹

Study design
The ARMANI trial is an open-label, multicenter, phase III study in which patients with HER2-negative advanced gastric or GEJ cancer, who did not experience disease progression after 3 months of first-line treatment with a platinum/fluoropyrimidine chemotherapy regimen (either FOLFOX or CAPOX), were randomized 1:1 to either ramucirumab plus paclitaxel (arm A) or an additional 3 months of CAPOX/FOLFOX chemotherapy followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), the percentage of patients receiving second-line therapy according to arm treatment, and safety. Biomarker status of Claudin 18 (CLDN18), PD-L1 CPS, and deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) were assessed by immunohistochemistry for exploratory analysis.

Results
A total of 280 patients were randomized into arm A (N=144) or arm B (N=136) with a median follow-up of 43.7 months (IQR: 24.0-57.9). The median PFS was significantly longer in arm A compared to arm B (6.6 vs. 3.5 months; HR [95%-CI]: 0.63 [0.49-0.81]; p<0.001). The 24-month restricted mean survival time analysis showed a significant 2.4-month average increment (P=0.002). The median OS was also significantly longer in arm A compared to arm B (12.6 vs. 10.4 months; HR [95%-CI]: 0.75 [0.58-0.97]; P=0.030). The PFS and the OS improvements were observed across all clinical subgroups in arm A. Patients in arm A received more treatments overall: 58% receiving ≥3 lines of treatment compared to 56% in arm B who received ≥2 treatments. Toxicity was higher in arm A, with 40.4% experiencing a grade ≥3 adverse event compared to 20.7% in arm B. Treatment burden was also higher in arm A due to the need for hospital visits to administer paclitaxel. There was no significant interaction between CLDN18 or PD-L1 expression status and treatment for both PFS and OS.

Conclusions
For patients with HER2-negative advanced gastric or GEJ cancer and disease control after 3 months of induction chemotherapy with FOLFOX or CAPOX, switch maintenance with paclitaxel and ramucirumab significantly prolonged PFS and OS compared to continued oxaliplatin-based chemotherapy. The PFS improvement was observed across all clinical and molecular subgroups. The ARMANI treatment strategy may represent a new first-line option for patients who are ineligible for targeted therapies or TFOX, although higher toxicity and treatment burden must be considered.

Reference

1. Randon G, et al. Switch maintenance with ramucirumab plus paclitaxel versus continuation of oxaliplatin-based chemotherapy in advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: final results and key biomarkers of the ARMANI phase III trial. Presented during ESMO WCGI, abstract LBA4.