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Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase 3 trial - 03/12/24

Doi : 10.1016/S1470-2045(24)00580-1 
Giovanni Randon, MD a, Sara Lonardi, MD b, Matteo Fassan, ProfMD c, d, Federica Palermo, BS a, Stefano Tamberi, MD e, Elisa Giommoni, MD PhD f, Carlotta Ceccon, BS c, Samantha Di Donato, MD PhD g, Lorenzo Fornaro, MD h, Oronzo Brunetti, MD i, Ferdinando De Vita, MD j, Alessandro Bittoni, MD k, Claudio Chini, MD l, Andrea Spallanzani, MD PhD m, Floriana Nappo, MD b, Valerie Bethaz, MD n, Antonia Strippoli, MD o, Tiziana Latiano, MD p, Giovanni Gerardo Cardellino, MD q, Francesco Giuliani, MD i, r, Federica Morano, MD a, Monica Niger, MD a, Alessandra Raimondi, MD a, Michele Prisciandaro, MD PhD a, Chiara Carlotta Pircher, MD a, Carolina Sciortino, MD a, Silvia Marchesi, MD a, Silvio Ken Garattini, MD a, q, Giulia Airò, MD a, s, Rosalba Miceli, BS PhD t, Maria Di Bartolomeo, MD a, Filippo Pietrantonio, MD a, ⁎
a Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 
b Department of Oncology, Veneto Institute of Oncology Istituto Oncologico Veneto-IRCCS, Padua, Italy 
c Surgical Pathology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy 
d Veneto Institute of Oncology IOV-IRCCS, Padua, Italy 
e Oncology Unit, Santa Maria delle Croci Hospital, Azienda Unità Sanitaria Locale della Romagna, Ravenna, Italy 
f Medical Oncology Unit, Careggi University Hospital, Florence, Italy 
g Medical Oncology Department ASL Toscana Centro, Santo Stefano Hospital, Prato, Italy 
h Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy 
i Istituto Tumori “Giovanni Paolo II” of Bari IRCCS, Bari, Italy 
j Division of Medical Oncology, Department of Precision Medicine, University of Campania “L Vanvitelli”, Naples, Italy 
k Oncology Unit, Istituto Romagnolo Per Lo Studio Dei Tumori “Dino Amadori” IRCCS, Meldola, Italy 
l Department of Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy 
m Department of Oncology and Haematology, Division of Oncology, University Hospital of Modena, Modena, Italy 
n Department of Oncology, “San Luigi Gonzaga” University Hospital, University of Turin, Orbassano, Italy 
o Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy 
p Department of Oncology, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia, Italy 
q Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy 
r Medical Oncology Unit, San Paolo Hospital, Bari, Italy 
s Department of Medicine and Surgery, University of Parma, Parma, Italy 
t Unit of Biostatistics for Clinical Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 

* Correspondence to: Dr Filippo Pietrantonio, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori Milan 20133 Italy

Summary

Background

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy.

Methods

ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete.

Findings

Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0–57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9–7·8) in the switch maintenance group and 3·5 months (2·8–4·2) in the control group (HR 0·61, 95% CI 0·48–0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7–9·9) in the switch maintenance group and 6·1 months (5·0–7·2) in the control group (p=0·0010). The most frequent grade 3–4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred.

Interpretation

Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents.

Funding

Partly funded by Eli Lilly.

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Vol 25 - N° 12

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