For patients with advanced HER2-negative gastric/ gastroesophageal junction (GEJ) cancer with low or absent PD-L1 expression, a platinum/fluoropyrimidine doublet is the standard of care for first-line therapy. At present, the addition of immune checkpoint inhibitors are not approved or recommended in several countries. In general, switch consolidation maintenance may prolong the benefit of the initial treatment strategy, and thus the ARMANI study compared switch maintenance with paclitaxel and ramucirumab to continuation of first-line oxaliplatin-based doublet chemotherapy.
This patient population (HER2-negative gastric/GEJ cancer with low/absent PD-L1 expression) presents an opportunity to improve outcomes and also the chance of receiving a second-line therapy, which currently sits at approximately 40% in clinical trials. It has been previously shown that the addition of the anti-VEGFR2 monoclonal antibody ramucirumab to the standard of care in first-line therapy did not improve progression-free survival (PFS) or overall survival (OS). Despite this, the standard second-line therapy in HER2-negative disease is paclitaxel and ramucirumab and warrants further investigation as a post-induction strategy.
The ARMANI study enrolled 280 patients with unresectable locally advanced or metastatic histologically confirmed HER2-negative gastric/GEJ adenocarcinoma without disease progression after three months of initial oxaliplatin-based chemotherapy. These patients were randomised 1:1 into arm A (paclitaxel 80 mg/sqm d1, 8, 15 + ramucirumab 8 mg/kg d1, 15, Q4W), or arm B (continuation of FOLFOX/CAPOX for 3 months followed by fluoropyrimidine maintenance). The primary endpoint was PFS, while OS was set as the secondary endpoint.
At a median follow up of 43.7 months, patients in arm A had a PFS of 6.6 months (95% CI[6-7.8]) vs. 3.5 months (2.8-4.2) in arm B (HR[95% CI] 0.64[0.49-0.81], p< 0.001). A similar benefit of paclitaxel + ramucirumab was also noted on OS (Arm A: 12.6 months (11.5-15); Arm B 10.4 months (8-13.1); HR[95% CI] 0.75[0.58-0.97], p= 0.028). In total, 58% of patients from arm A and 56% from arm B went on to receive a subsequent therapy. Interestingly, the main choice for patients of arm B was paclitaxel + ramucirumab (45%) where 37% of patients from arm A went on to receive irinotecan/FOLFIRI/CAPIRI. Overall response rate was also higher in arm A vs. Arm B (18.9% vs. 15.7%), with a disease control rate that was significantly higher in arm A (85.3% vs. 54%). In terms of safety, 40.4% of patients in arm A experienced grade 3 or higher treatment-related adverse events (TRAE) vs. 20.7% from arm B. The most observed grade 3 or higher TRAE was neutropenia (arm A: 26.2%; arm B: 9.6%).
In conclusion, in patients with advanced HER2-negative gastric/GEJ cancer and disease control after FOLFOX/CAPOX for 3 months, switch maintenance with paclitaxel + ramucirumab significantly improved the PFS and OS vs. continuation of oxaliplatin-based chemotherapy. This was associated with a higher incidence of grade 3 or more TRAEs, but the safety profile was consistent with the literature and no unexpected safety signals were observed. Switch maintenance with paclitaxel and ramucirumab may therefore be beneficial for patients who are ineligible for treatment with immune checkpoints inhibitors.
Reference
Pietrantonio F, et al. 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. Presented at ASCO 2024; Abstract LBA4002.
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