SAN FRANCISCO — Adding ziv-aflibercept to FOLFOX regimens did not significantly improve survival among patients with chemotherapy-naïve metastatic esophagogastric adenocarcinoma, according to data from a phase 2 randomized trial presented at the Gastrointestinal Cancers Symposium.
Based on previous data, modified FOLFOX6 was chosen as the “standard chemotherapy backbone for this trial. … We wished to combine this standard chemotherapy with an anti-VEGF inhibitor,” Peter C. Enzinger, MD, from the Dana-Farber Cancer Institute in Boston, said during his presentation.
“Ziv-aflibercept, a recombinant fusion protein fusing the VEGF binding portions from the extracellular domains of human VEGF R-1 and -2 to the FC portion of human IGG-1 immunoglobulin, had been tested in the VELOUR study,” he said. “This was a study in refractory metastatic colorectal cancer in which FOLFIRI plus ziv-aflibercept vs. FOLFIRI plus placebo was tested. Ziv-aflibercept improved overall survival with a hazard ratio of 0.82 and a P value of .032. Hence, we decided to add ziv-aflibercept to the FOLFOX regimen. I should note that the positive results of REGARD and RAINBOW with ramucirumab had not yet been presented when we initiated this study.”
Among 64 patients enrolled from January 2013 through April 2015, 55 were men, median age was 62 years, and the primary tumor site was the esophagus in 26 patients, gastroesophageal (GE) junction in 18 and gastric in 20. Minimum follow-up was 8 months, and 52 had measurable disease.
“Inclusion criteria included histologically confirmed, unresectable esophageal, GE junction or gastric adenocarcimoma,” Enzinger said. “Measurable disease was not required. Patients had to have an ECOG performance status of two or higher and they all had to have adequate organ function. Exclusion criteria included prior chemotherapy, except as part of pre- or postoperative therapy completed at least 1 year prior to the start date of this protocol, squamous cell carcinoma histology, standard FOLFOX exclusion criteria and standard VEGF inhibitor exclusion criteria.”
All patients received mFOLFOX6 every 2 weeks (or every 14 days), and 43 were randomized to receive 4 mg/kg ziv-aflibercept (Zaltrap, Sanofi Aventis) and 21 to placebo. Patients were restaged every 8 weeks and 6-month progression-free survival (PFS) served as the primary endpoint.
Overall, 60.5% of the ziv-aflibercept arm achieved 6-month PFS vs. 57.1% of the placebo arm (P = .8). Moreover, 58.7% vs. 55.1% achieved 1-year OS, major response rates were 61% vs. 75%, median PFS was 9.9 vs. 7.3 months (P = .69) and median OS was 13.7 vs. 18.7 months.
Grade 3/4 treatment-emergent adverse events occurred in 5% or more of patients, and the most common toxicity was hypertension, occurring in 47% vs. 5%, respectively (P = .0006). There was no significant difference in other toxicities, and death on treatment was similar (7% vs. 5%).
“Candidly, these results came as a surprise to us because patients with grade 3 hypertension did remarkably well in this study,” Enzinger said. “We therefore decided to do an exploratory post hoc analysis of patients on ziv-aflibercept with grade 3 hypertension or not.”
The major response rate for patients with grade 3 hypertension on ziv-aflibercept was 100%, while for patients with grade 0 to 2 hypertension, major response rate was 36% (P < .0001). Moreover, 6-month progression-free survival (PFS) was 79% vs. 45.8% (P = .02) and there was a trend to improved 1-year OS (71.4% vs. 48.7%). Median PFS was 10.9 vs. 5.8 months (P = .04) and median OS was 17.5 vs. 11.9 months.
“In conclusion, I think we can say ziv-aflibercept did not significantly improve the efficacy of the FOLFOX regimen,” Enzinger said. “Both arms were well tolerated with an expected increase in hypertension among the ziv-aflibercept treated patients. Nearly half of the patients on ziv-aflibercept developed grade 3 hypertension. The potential improved outcome for patients on ziv-aflibercept with grade 3 hypertension vs. grade 0 [to] 2 should be examined in similar trials of anti-VEGF therapy.” – by Adam Leitenberger
Enzinger PC, et al. Abstract 04. Presented at: Gastrointestinal Cancers Symposium; Jan. 21-23, 2016; San Francisco.
Disclosure: Enzinger reports consulting or advisory roles for Amgen, Five Prime Therapeutics, Pfizer, Sirtex Medical and Taiho Pharmaceutical. Please see the full abstract for a list of all other researchers’ relevant financial disclosures.
Editor's Note: This article was updated on Feb. 15 to reflect additional information.