Oral apatinib conferred a small but statistically significant OS and PFS benefit among patients with gastric cancer who failed two or more lines of chemotherapy, according to results of a randomized phase 3 trial.
Gastric cancer is the third leading cause of cancer-related deaths worldwide. However, there is no standard treatment for patients with advanced metastatic gastric cancer who progressed after two or more lines of chemotherapy, according to study background.
David H. Ilson
In a phase 2 study, apatinib (YN968D1, LSK BioPharma) — a novel, small-molecule tyrosine kinase inhibitor that selectively inhibits VEGFR-2 — improved OS and PFS in patients with chemotherapy-refractory advanced or metastatic gastric carcinoma compared with placebo.
To further confirm the agent’s efficacy, Jin Li, MD, of Fudan University Shanghai Cancer Center, and colleagues conducted a randomized, double blind, placebo-controlled phase 3 trial of apatinib in patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who failed at least two lines of systemic chemotherapies.
OS and PFS served as primary endpoints. Secondary endpoints included objective response rate, disease control rate, quality of life and safety.
Researchers enrolled 267 patients from 32 centers in China. Investigators randomly assigned patients 2:1 to either 850 mg of oral apatinib or placebo once daily.
Each treatment cycle lasted 4 weeks, and treatment continued until patients experienced disease progression, developed intolerable toxicity or withdrew consent. Patients assigned apatinib received an average of 2.9 treatment cycles, and those assigned placebo received an average of 1.89 cycles.
At data cutoff, 83% of the 176 patients assigned apatinib and 85.7% of the 91 patients assigned placebo group had died.
Results showed patients assigned apatinib achieved significantly longer median OS (6.5 months vs. 4.7 months; HR = 0.71, 95% CI, 0.54-0.93) and median PFS (2.6 months vs. 1.8 months; HR = 0.44, 95% CI, 0.33-0.56) than patients assigned placebo.
Researchers observed a significantly higher objective response rate (2.84% vs. 0%) and disease control rate (42.05% vs. 8.79%) among patients assigned apatinib (P < .001). Investigators reported no significant difference in quality-of-life scores between groups.
Patients assigned apatinib experienced higher rates of any-grade leukopenia (40.3% vs. 8.8%), neutropenia (37.5% vs. 9.9%), thrombocytopenia (25% vs. 6.6%), proteinuria (47.7% vs. 16.5%) hypertension (35.2% vs. 5.5%) and hand–foot syndrome (27.8% vs. 2.2%).
The primary reasons for dose reduction in the apatinib group were grade 3 to grade 4 hand–foot skin reaction (8.5%), hypertension (4.5%) or proteinuria (2.3%).
“These data demonstrate that apatinib could be a new treatment option for patients with metastatic gastric cancer experiencing progression after two or more lines of chemotherapy,” Li and colleagues wrote. “A series of additional studies designed to assess the potential application of apatinib in other solid tumors, such as non–small cell lung cancer and hepatocellular carcinoma, is ongoing.”
Results of this trial and others show the VEGF pathway is a viable therapeutic target in gastric cancer, David H. Ilson, MD, PhD, a member of the gastrointestinal cancer service at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, wrote in an accompanying editorial.
However, recent clinical trials in gastric cancer have yielded “incremental but modest gains,” he wrote.
“The modest survival improvement achieved with agents like apatinib ... requires study of the relative cost vs. the benefit,” Ilson wrote. “In later-line therapy trials, given the poor short-term survival, although small incremental improvements with new therapies translate into impressive hazard ratios that achieve statistical significance, are they clinically meaningful?”
Recent results will shape future trials in esophagogastric cancer, both in advanced disease and the adjuvant setting, Ilson wrote.
“Using less toxic regimens, potentially for a shorter duration, will enhance the opportunity to combine novel agents with systemic chemotherapy and will potentially allow the introduction of novel therapeutic strategies earlier on in the adjuvant setting,” he wrote. – by Kristie L. Kahl
Disclosure: Li reports research funding from Amgen and Merck. Please see the full study for a list of all other researchers’ relevant financial disclosures. Ilson reports consultant roles with Amgen, Eli Lilly/ImClone and Roche/Genentech; a speakers bureau role with Eli Lilly/ImClone; research funding from Amgen, Bayer and Bristol-Myers Squibb; and accommodations from Amgen and Eli Lilly/ImClone.