In patients with advanced HER2-negative gastric or gastroesophageal junction cancer and disease control after oxaliplatin-based chemotherapy, “switch” maintenance with paclitaxel plus ramucirumab in the phase III ARMANI trial significantly improved both progression-free and overall survival, compared with continuing on the same chemotherapy.1
“Switch maintenance with paclitaxel plus ramucirumab may be a novel postinduction strategy in patients who are not eligible for upfront treatment with immune checkpoint inhibitors,” said Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy. “The experimental strategy produced a higher rate of grade ≥ 3 treatment-related adverse events, but the safety profile was consistent with the literature, and no unexpected safety signals were observed.”
Filippo Pietrantonio, MD
At a median follow-up of 43.7 months, switch maintenance resulted in a median progression-free survival of 6.6 months, vs 3.5 months with continuation of first-line chemotherapy (hazard ratio [HR] = 0.64; P < .001). The 24-month restricted mean survival time analysis showed a 2.4-month average increment, which was statistically significant (P = .002). Median overall survival was 12.6 vs. 10.4 months, respectively (HR = 0.75; P = .028).
At the 2024 ASCO Annual Meeting, Dr. Pietrantonio explained that for gastric or gastroesophageal junction HER2-negative tumors with little to no expression of PD-L1, platinum/fluoropyrimidine doublets are a standard first-line therapy. Although immune checkpoint inhibitors might be used in this patient population in some countries, these drugs are not recommended by several guidelines. Outcomes after first-line therapy are often unfavorable, and many patients—more than half even in recent phase III studies—do not receive second-line therapy. The rationale for switch consolidation and maintenance is to prolong the benefit of the initial therapy and delay clinical deterioration. In the ARMANI trial, paclitaxel/ramucirumab was the switch therapy tested for this purpose.
ARMANI Design and Outcomes
The phase III trial enrolled 280 patients whose disease was controlled after 3 months of induction with either FOLFOX (fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin). Patients were randomly assigned to the experimental arm of paclitaxel plus ramucirumab or continuation of the first-line chemotherapy with standard-of-care dose adjustments as needed.
ARMANI met both its primary endpoint of progression-free survival (> 90% of events occurring) and the key secondary endpoint of overall survival (> 85% of events occurring). Overall survival was significantly improved with paclitaxel/ramucirumab despite the fact that 45% of the control arm ultimately received this regimen as well. A similar percentage of patients in each arm received some form of subsequent therapy.
Postinduction objective responses were similar between the two arms, but the disease control rate was numerically higher in the switch maintenance group.
Safety Profile
The frequency of grade ≥ 3 adverse events was 40.4% in the experimental arm vs 20.7% in the control arm, mainly neutropenia (26.2% and 9.6%), febrile neutropenia (1.4% and 0%), hypertension (6.4% and 0%), venous thromboembolism (2.8 and 0%), and peripheral neuropathy (5.7% and 6.7%). No treatment-related deaths were reported.
“Translational analyses are ongoing, and the efficacy of the ARMANI strategy in clinically relevant subgroups will be reported in future meetings,” Dr. Pietrantonio said.
Expert Point of View
The invited discussant of the phase III ARMANI trial, Nataliya Uboha, MD, PhD, of the University of Wisconsin Carbone Cancer Center, Madison, said the investigators “attempted to ask the question of whether moving second-line therapy with ramucirumab and paclitaxel to an earlier line as consolidation or switch maintenance provides better outcomes.” The question is important, she said, since as many as half of these patients never receive second-line therapy, even in contemporary clinical trials.
The result of the switch maintenance strategy was an improvement in progression-free and overall survival as compared to continuing oxaliplatin-based chemotherapy—but at the cost of more toxicity. “The goal with maintenance therapy is to control the disease, but to also allow patients to recover from toxicities from induction therapy—to maintain quality of life and to hopefully give them a little break from seeing us in the clinic,” Dr. Uboha said. The schedule of administration of ramucirumab (8 mg/kg on days 1 and 15) and paclitaxel (80 mg/m2 on days 8 and 15) is more intense than what is typically provided with FOLFOX (leucovorin, fluorouracil, oxaliplatin), she noted.
She pointed out that the study’s enrollment began in 2017, and since then a number of new biomarkers, such as PD-L1, have become considerations in clinical practice. “Our first-line treatments for patients with this disease have changed, and we are incorporating more and more biomarker-based therapies and immunotherapies. There will be a decreasing fraction of patients treated with chemotherapy alone in the first-line setting,” Dr. Uboha said. The approach that met with success in ARMANI, she added, “may benefit some patients, especially those with biomarker-negative tumors … but I would be worried about adopting this strategy in patients who are responding to first-line chemotherapy and having good tolerance to treatment.”
DISCLOSURE: Dr. Pietrantonio has served as a consultant or advisor to Amgen, Bayer, GlaxoSmithKline, Janssen, Merck Serono, MSD Oncology, Rottapharm Biotech, Servier, and Takeda; and has received honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Ipsen, Johnson & Johnson, Merck Serono, MSD Oncology, Pierre Fabre, Rottapharm Biotech, Seagen, Servier, and Takeda; institutional research funding from Agenus, Amgen, AstraZeneca, Bristol Myers Squibb, Incyte, and Lilly; and compensation for travel, accommodations, or other expenses from Merck Serono and Pierre Fabre. Dr. Uboha reported financial relationships with Aptitude Health, Arcus Biosciences, Astellas Pharma, AstraZeneca, BostonGene, Bristol Myers Squibb/Roche, BMS Foundation, Eisai/MSD, Elevation Oncology, GRAIL, Helsinn Therapeutics, Ipsen, Lilly, Pfizer, and Strata Oncology.
REFERENCE
1. Pietrantonio F, Randon G, Lonardi S, et al: Ramurirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastroesophageal junction cancer: The ARMANI phase III trial. 2024 ASCO Annual Meeting. Abstract LBA4002. Presented June 4, 2024.
