Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial.
Authors: Filippo Pietrantonio, Giovanni Randon, Sara Lonardi, Silvio Ken Garattini, Stefano Tamberi, Elisa Giommoni, Samantha Di Donato, Lorenzo Fornaro, Oronzo Brunetti, Ferdinando De Vita, Giovanni Luca Frassineti, Claudio Chini, Andrea Spallanzani, Valerie Bethaz, Antonia Strippoli, Tiziana Pia Latiano, Giovanni Gerardo Cardellino, Federica Palermo, Rosalba Miceli, Maria Di Bartolomeo
Journal: Journal of Clinical Oncology (2024)

LBA4002 Background: In pts with HER2-negative advanced gastric/GEJ cancer and PD-L1 low/absent expression, platinum/fluoropyrimidine doublets are a standard first-line therapy. In this patient population, the outcomes are unsatisfactory and second-line therapy is given in only 40% of clinical trial patients. Switch consolidation maintenance may prolong the benefit of the initial strategy and delay clinical deterioration. Despite ramucirumab failing to prolong both progression-free survival (PFS) and overall survival (OS) in the first-line setting, paclitaxel plus ramucirumab is a standard second-line therapy and warrants investigation as a post-induction strategy. Methods: Pts with HER2-negative advanced gastric/GEJ cancer without disease progression after 3 months of initial oxaliplatin-based chemotherapy, stratified by site of origin (GEJ vs gastric), prior gastrectomy and peritoneal disease, were randomized 1:1 to ramucirumab 8 mg/Kg on days 1,15 plus paclitaxel 80 mg/sqm on days 1,8,15 every 28 days (arm A) vs CAPOX/FOLFOX at the same doses used in the last induction cycle, for additional 3 mos followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was PFS, OS was a key secondary endpoint; quality of life, safety, and biomarkers were evaluated. A sample size of 280 pts achieved a 90% power to detect as significant at a 5% level (2-sided log-rank test) a median PFS increase from 4 to 6 mos (target HR=0.67). HRs were estimated by Cox models adjusting for stratification factors. Restricted Mean Survival Time (RMST) analysis was conducted in case of violation of proportional hazards assumption. Results: From Jan 2017 to Oct 2023, 280 patients were randomly assigned (144 arm A/136 arm B). Baseline characteristics were: male sex 67/61%, median age 64/66 years, PS 0 74/65%, GEJ 26/26%, prior gastrectomy 28/23%, peritoneal metastases 53/42%. At a median follow-up of 43.7 months (IQR 22.0-57.9), median PFS was 6.6 vs. 3.5 mos in Arm A vs. B (HR=0.63, 95%CI 0.49-0.81; P&lt;0.001). 24-mos RMST analysis showed a statistically significant 2.4-mos average increment (p=0.002). Median OS was 12.6 vs. 10.4 mos in Arm A vs. B (HR=0.75, 95%CI 0.58-0.97; P=0.030). The frequency of grade ≥3 adverse events was 40.4% vs. 20.7% in arms A vs. B, respectively, mainly neutropenia 25.5/9.6%; febrile neutropenia 2.1/0%; hypertension 6.4/0%; venous thromboembolism 2.1/0%; peripheral neuropathy 5.7/6.7%. No treatment-related deaths were reported. Conclusions: Switch maintenance with paclitaxel plus ramucirumab after 3 months of oxaliplatin-based doublets may be a new strategy in patients with HER2-negative metastatic gastric/GEJ cancer who are non-eligible for initial immune checkpoint inhibitor-based regimens according to specific guidelines and regulatory approvals. Clinical trial information: NCT02934464 .