Adding Ziv-Aflibercept to Topotecan Improves Progression-Free Survival but Increases Toxicity in Platinum-Treated Small Cell Lung Cancer
The phase II Southwest Oncology Group (SWOG) S0802 trial reported in the Journal of Clinical Oncology by Allen et al showed that adding ziv-aflibercept (Zaltrap) to topotecan improved 3-month progression-free survival, but increased toxicity and had no effect on overall survival, in patients with platinum-treated small cell lung cancer (SCLC).
Study Details
In the trial, 189 patients who had experienced disease progression after one line of platinum-based chemotherapy and had treated brain metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, and no recent vascular events or bleeding diatheses were randomly assigned to receive weekly topotecan at 4 mg/m2 with (n = 97) or without (n = 92) ziv-aflibercept at 6 mg/kg every 21 days. Patients were stratified as platinum-refractory (n = 55 vs 51) or platinum-sensitive (n = 42 vs 41). Progression-free survival at 3 months was the primary endpoint.
The ziv-aflibercept and control patients in the platinum-sensitive (n = 83) and platinum-resistant (n = 106) subgroups were generally balanced for age (medians, 63 vs 60 years; 61 vs 64 years), sex (60% vs 68% female; 53% vs 33% female), ethnicity (86% vs 98% white; 89% vs 84% white), metastatic disease site (eg, multiple lesions and multiple organs in 69% vs 54%; 75% vs 67%), and disease stage (extensive in 64% vs 56%; 71% vs 82%).
Increased 3-Month Progression-Free Survival
Three-month progression-free survival was significantly improved with ziv-aflibercept in the platinum-refractory subgroup (27% vs 10%, P = .02) but not in the platinum-sensitive subgroup (24% vs 15%, P = .22). Median overall survival was 4.6 months vs 4.2 months (P = .37) in the platinum-refractory subgroup and 6.0 vs 4.6 months (P = .36) in the platinum-sensitive subgroup. Among all patients, 3-month progression-free survival was 26% vs 12% (P =.01) and median overall survival was 5.4 vs 4.4 months.
Only a few objective responses were observed. The disease control rate was numerically higher among ziv-aflibercept patients in the platinum-refractory subgroup (25% vs 15%, P = .14) and in the platinum-sensitive subgroup (37% vs 18%, P = .05).
Toxicity
Grade 3 to 5 nonhematologic toxicities were more common with the addition of ziv-aflibercept (43% vs 14%, P < .001), including a greater frequency of fatigue (16% vs 3%). Grade 4 neutropenia occurred in 3.2% vs 5.7% of patients. Grade 5 events occurred in one patient in the ziv-aflibercept group (pulmonary hemorrhage) and three patients in the control group (infection in two, renal failure in one).
Characteristic VEGF-related adverse events were observed at generally low rates in the ziv-aflibercept group; grade 3 or higher hemorrhage occurred in 6.4% of patients. Discontinuation of treatment due to adverse events was more common in the ziv-aflibercept group (18% vs 6%), including both the platinum-refractory subgroup (18% vs 10%, P = .22) and particularly the platinum-sensitive subgroup (19% vs 2%, P = .045.)
The investigators concluded, “Ziv-aflibercept improved the 3-month [progression-free survival] in patients who had platinum-refractory SCLC, but its addition increased toxicity. [Overall survival] was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata.”
Jeffrey Allen, MD, of the University of Tennessee Health Science Center, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Public Health Service Cooperative Agreement grants from the National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.
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