Abstract
BACKGROUND:
Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adeno-carcinoma.
METHODS:
Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS).
RESULTS:
Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treat-ment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort.
CONCLUSIONS:
Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocar-cinoma is not warranted.
Keywords: angiogenesis, esophageal cancer, folinic acid, fluorouracil, oxaliplatin (FOLFOX), gastric cancer, ziv-aflibercept
INTRODUCTION
Metastatic esophagogastric adenocarcinoma is an incurable malignancy with limited treatment options.1 First-line regimens generally use a platinum and fluoropyrimidine backbone and result in a median progression-free survival (PFS) of approximately 5 to 7 months.2,3 Based in part on results from CALGB 80403 (Alliance)/E1206, modified FOLFOX6 (mFOLFOX6), a combination of oxaliplatin, leucovorin, and bolus plus infusional 5-fluorouracil, has become the most commonly used regimen in the United States for metastatic esophagogastric cancer.3,4
Regimens combining cytotoxic chemotherapy and antiangiogenic therapy have proven to be effective in treating lung and colorectal cancers. Potential mechanisms explaining the ability of antiangiogenic drugs to enhance the efficacy of cytotoxic chemotherapy include immune modulation and increased drug exposure through the normalization of intratumoral blood vessels.5 In the setting of esophagogastric cancer, clinical trials have demonstrated that ramucirumab, a monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR2), administered as a single agent or with paclitaxel, significantly prolongs survival when it is given as second-line therapy to patients with metastatic gastric and gastroesophageal junctional adenocarcinoma.6,7 Furthermore, a trial of apatinib, a VEGFR2 tyrosine kinase inhibitor, has suggested improved survival for patients with refractory gastric or gastroesophageal junction adenocarcinoma.8
Despite these encouraging findings in the refractory disease setting, randomized trials assessing antiangiogenic therapy in combination with standard front-line chemotherapy have failed to extend survival when it has been used as the initial treatment for patients with esophagogastric adenocarcinoma (AVAGAST, AVATAR, and RAINFALL).9–11
Ziv-aflibercept is a recombinant fusion protein that binds vascular endothelial growth factor A (VEGF-A), VEGF-B, and placental growth factor with a high affinity.12 The phase 3 VELOUR study demonstrated that the addition of ziv-aflibercept to second-line irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) prolonged survival in previously treated patients with metastatic colorectal cancer.13 We hypothesized that ziv-aflibercept would enhance the activity of first-line mFOLFOX6 in esophagogastric adenocarcinoma. Here we report the results of the ZAMEGA trial, a randomized phase 2 trial that evaluated the safety and efficacy of adding ziv-aflibercept to first-line mFOLFOX6 for metastatic esophagogastric adenocarcinoma.
MATERIALS AND METHODS
Study Population
Eligible patients were adults who had histologically confirmed metastatic adenocarcinoma of the esophagus, gastroesophageal junction, or stomach. Patients may not have received any prior chemotherapy for their advanced disease, although we did include patients who had completed neoadjuvant or adjuvant treatment at least 1 year before study entry. Patients who had finished palliative radiation 2 (<25% of bone marrow) or 4 weeks (≥25% of bone marrow) before enrollment were eligible for the trial.
Eligible patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Measurable disease was not required. Adequate renal, hematologic, and liver function was mandated. Therapeutic anticoagulation with low–molecular weight heparin was allowed. Major exclusion criteria included brain metastases, symptomatic congestive heart failure, myocardial infarction, grade 2 or higher neuropathy, and uncontrolled bleeding. Hypertension must have been adequately controlled with antihypertensive medication with a blood pressure less than 150/100 mm Hg.
Study Design
The ZAMEGA trial (NCT01747551) was a multicenter, double-blind randomized controlled trial that assigned patients in a 2:1 ratio to receive mFOLFOX6 and ziv-aflibercept or mFOLFOX6 and a placebo. Randomization was stratified by the ECOG performance status (0–1 vs 2) and the primary site of disease (esophagus or gastroesophageal junction vs stomach). This trial was approved by the internal review board of the Dana-Farber/Harvard Cancer Center and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All patients signed an internal review board–approved consent form before enrollment.
Treatment Protocols
Patients received mFOLFOX6 and ziv-aflibercept or a placebo every 2 weeks. Ziv-aflibercept (4 mg/kg) or the placebo was administered intravenously over 1 hour, and it was followed immediately by mFOLFOX6 given according to the institutional standard: intravenous oxaliplatin (85 mg/m2) and intravenous leucovorin (400 mg/m2) were administered concurrently over 120 minutes, and they were followed by an intravenous bolus injection of fluorouracil (400 mg/m2) and then an intravenous infusion of fluorouracil (2400 mg/m2) over 46 hours. Investigators followed institutional guidelines for premedications, antiemetics, and growth factor utilization. Ziv-aflibercept could be dose-reduced once to 2 mg/kg, and mFOLFOX6 could be dose-reduced according to the investigator’s discretion. Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Patients continued the protocol treatment until radiological or clinical progression, unacceptable toxicity, or death. No crossover was allowed between arms. The study remained blinded until November 2, 2015, when all patients had been enrolled in the trial for at least 6 months. Adverse-event assessments were made according to the Common Toxicity Criteria for Adverse Events (version 4.0).
Statistical Analyses
The primary endpoint was the assessment of PFS at 6 months. PFS was measured from the date of randomization to the first objective documentation of progressive disease or the date of death. Patients who discontinued treatment without documented progressive disease were followed and included in the PFS analysis until documented progression, death from any cause, or the initiation of new anticancer therapy, at which point they were censored. The study was designed to have 80% power at a 0.20 significance level to detect a difference in 6-month PFS of 15%, which corresponded to an improvement from 50% to 65%.
Secondary objectives of the trial included an evaluation of safety and tolerability, the objective response rate (complete responses plus partial responses), and overall survival (OS). Comparisons of response rates between arms were made with Fisher exact tests. OS was defined as the time between randomization and death. Kaplan-Meier methodology was used to obtain survival estimates. Survival at 6 months and median survival were compared between arms with the log-rank test. Hazard ratios were compared with Cox proportional hazards models.
The relative dose intensity of chemotherapy was calculated as the ratio of the actual cumulative dose that a patient received to the protocol-specified cumulative dose over the specified time period.14 The proto-col-specified dose was determined by calculation of the cumulative amount of chemotherapy planned by the protocol. For patients who prematurely stopped che-motherapy because of disease progression or death, the protocol-specified cumulative dose was calculated on the basis of the duration of treatment. For patients who discontinued treatment for reasons other than progression or death before the first 12 or 24 weeks of protocol treatment, the protocol-specified cumulative dose was calculated with the protocol-planned chemotherapy dose over a 12- (or 24-) week duration.14 The mean relative dose intensity was compared between treatment arms with t tests.
RESULTS
Between January 2013 and April 2015, 64 eligible patients were randomly assigned to receive mFOLFOX6/ ziv-aflibercept (43 patients) or mFOLFOX6/placebo (21 patients; Fig. 1). All registered patients received at least 1 cycle of treatment. The demographic and disease characteristics of the patients at the baseline were reasonably balanced between the 2 treatment groups (Table 1). Patients were evenly distributed by the ECOG performance status (0–1 vs 2) and the primary site of disease (esophageal or gastroesophageal junction vs gastric) because of the stratification. The mFOLFOX6/ziv-aflibercept arm had a higher percentage of patients with esophageal cancer (37% vs 24%) and patients with an ECOG score of 0 (56% vs 38%), but neither of these differences was statistically significant (P = .40 and P = .29, respectively).
Figure 1.
Consolidated Standards of Reporting Trials diagram.
TABLE 1.
Baseline Patient Characteristics
| Characteristic | mFOLFOX6/Ziv-Aflibercept (n = 43) | mFOLFOX6/Placebo (n = 21) |
|---|---|---|
| Age, y | ||
| Median | 62 | 62 |
| Range | 32−83 | 40−79 |
| Sex, No. (%) | ||
| Male | 37 (86) | 18 (86) |
| Female | 6 (14) | 3 (14) |
| Race, No. (%) | ||
| White | 41 (95) | 18 (86) |
| Black | 0 (0) | 1 (5) |
| Asian | 0 (0) | 1 (5) |
| Other | 2 (5) | 1 (5) |
| Performance status, No. (%) | ||
| ECOG 0 | 24 (56) | 8 (38) |
| ECOG 1 | 17 (40) | 12 (57) |
| ECOG 2 | 2 (5) | 1 (5) |
| Primary site, No. (%) | ||
| Esophagus | 16 (37) | 5 (24) |
| GE junction | 13 (30) | 10 (48) |
| Gastric | 14 (33) | 6 (29) |
| Measurable disease, No. (%) | 36 (84) | 16 (76) |
| Metastatic site, No. (%) | ||
| Lymph node | 31 (72) | 17 (81) |
| Liver | 18 (42) | 7 (33) |
| Peritoneal | 11 (26) | 7 (33) |
| Lung | 9 (21) | 6 (29) |
| Adrenal | 3 (7) | 1 (5) |
| Bone | 2 (5) | 1 (5) |
| HER2+, No. (%) | 1 (2) | 1 (5) |
Abbreviations: ECOG, Eastern Cooperative Oncology Group; GE, gastroe-sophageal; HER2, human epidermal growth factor receptor 2.
As of the data cutoff of July 26, 2017, all 64 patients had discontinued study treatment. The most common reason for being removed from the trial was progressive disease (64%). The median follow-up for patients in the trial was 15.5 months (range, 0.6–51.4 months). Patients in the mFOLFOX6/ziv-aflibercept arm received treatment for a median of 6.9 months, and patients in the mFOLFOX6/placebo arm received treatment for a median of 6.4 months.
Efficacy
The study did not meet its primary endpoint of prolonging 6-month PFS (P = .72). The 6-month PFS rate was 60.5% (95% confidence interval [CI], 44.3%−73.3%) for patients in the mFOLFOX6/ziv-aflibercept arm and 57.1% (95% CI, 33.8%−74.9%) for those in the mFOLFOX6/placebo arm. The hazard ratio for PFS (mFOLFOX6/ziv-aflibercept vs mFOLFOX6/placebo) was 1.11 (95% CI, 0.64–1.91; P = .72). The median PFS was 9.7 months (95% CI, 5.8–10.5 months) in the mFOLFOX6/ziv-aflibercept arm and 7.4 months (95% CI, 4.4–12.8 months) in the mFOLFOX6/placebo arm (P = .72; Fig. 2A).
Figure 2.
Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival for patients treated with mFOLFOX6/ziv-aflibercept or mFOLFOX6/placebo. The x-axes are truncated at 24 months from randomization.
There also was no significant difference in OS, with the median OS being 14.5 months (95% CI, 11.7–17.5 months) in the mFOLFOX6/ziv-aflibercept group and 18.8 months (95% CI, 7.8–23.0 months) in the mFOLFOX6/placebo group (P = .45; Fig. 2B). The hazard ratio for OS (mFOLFOX6/ziv-aflibercept vs mFOLFOX6/ placebo) was 1.24 (95% CI, 0.71–2.15; P = .45). The 1-year OS rate was 62.8% (95% CI, 46.6%−75.3%) for the mFOLFOX6/ziv-aflibercept arm and 57.1% (95% CI, 33.8%−74.9%) for the mFOLFOX6/placebo arm.
Similarly, there was no significant difference in the objective response rate (complete responses plus partial responses) between the 2 arms for patients with measurable disease (n = 52; P = .53). The objective response rate was 61.1% (95% CI, 43.5%−76.9%) in the mFOLFOX6/ziv-aflibercept group (n = 36) and 75.0% (95% CI, 47.6%−92.7%) in the mFOLFOX6/placebo group (n = 16).
Because the results of a phase 2 study of first-line oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) and ramucirumab indicated a benefit for angiogenic inhibition in patients with metastatic gastric and gastro-esophageal junctional cancer but not in those with pure metastatic esophageal cancer,15 we performed a post hoc subgroup analysis of these populations. Although the trial was not sufficiently powered to definitively analyze these populations, we did not observe any evidence that ziv-aflibercept preferentially enhanced the activity of mFOLFOX6 in patients with gastric adenocarcinoma, gastroesophageal junctional cancer, or pure esophageal adenocarcinoma (Table 2).
TABLE 2.
Subgroup Analysis of Efficacy Based on the Site of the Primary Tumor
| Progression-Free Survival, Median (95% CI), mo |
Overall Survival, Median (95% CI), mo |
|||||
|---|---|---|---|---|---|---|
| Site | Aflibercept | Placebo | P | Aflibercept | Placebo | P |
| Esophageal (n = 26) | 9.2 (5.5−11.1) | 9.6 (0.6−18.4) | .90 | 16.0 (9.0−18.1) | 18.8 (0.6−26.6) | .99 |
| Gastroesophageal junction (n = 18) | 9.9 (4.0−17.4) | 6.4 (2.8−14.5) | .94 | 16.8 (12.6−22.8) | 18.3 (4.9−26.9) | .83 |
| Gastric (n = 20) | 9.6 (4.5−10.9) | 7.4 (1.9−25.0) | .95 | 12.3 (6.6−15.3) | 15.0 (4.4−27.6) | .27 |
| Gastroesophageal junction and gastric (n = 38) | 9.9 (5.2−10.9) | 7.2 (3.9−13.3) | .77 | 14.1 (11.7−16.8) | 18.3 (6.9−26.4) | .39 |
Abbreviation: CI, confidence interval
Data on subsequent lines of therapy were available for 41 of the 43 patients in the mFOLFOX6/ ziv-aflibercept arm and for all of the patients in the mFOLFOX6/placebo arm. There was no significant difference between lines of subsequent therapy in the 2 arms (P = .75). In the mFOLFOX6/ziv-aflibercept arm, 80% received second-line therapy, 42% received third-line therapy, and 12% received 4 or more lines of therapy, whereas in the mFOLFOX6/placebo arm, 81% received second-line therapy, 48% received third-line therapy, and 14% received 4 or more lines of therapy. There also was no significant difference in subsequent treatment with ramucirumab (46% vs 57%; P = .59) or PD1-directed therapy (17% vs 24%; P = .52) between the mFOLFOX6/ziv-aflibercept arm and the mFOLFOX6/placebo arm.
Safety
Patients receiving mFOLFOX6/ziv-aflibercept tended to be more likely than mFOLFOX6/placebo patients to discontinue treatment for reasons other than progres-sive disease (44% vs 19%; P = .06). Eighty-one percent of the mFOLFOX6/placebo patients were removed from the study because of progressive disease, whereas 56% of the mFOLFOX6/ziv-aflibercept patients were. In comparison with the mFOLFOX6/placebo group, there appeared to be a greater number of mFOLFOX6/ziv-aflibercept patients who discontinued protocol treatment because of drug-related toxicity, prolonged treatment delays, or treatment-related death (26% vs 5%; P = .08).
Grade 3 or higher hypertension was observed more frequently in patients receiving mFOLFOX6/ziv-aflibercept than those in the mFOLFOX6/placebo arm (P = .0002). Rates of bleeding and thromboembolic events as well as episodes of heart failure and gastroin-testinal perforations were somewhat higher in patients receiving mFOLFOX6/ziv-aflibercept, but these differences were not statistically significant (Table 3).
TABLE 3.
Grade 3 to 5 Adverse Events at Least Possibly Related to the Study Treatment
| Grade 3 or Higher Event | Arm A (n = 43): mFOLFOX6/Ziv-Aflibercept, No. (%) | Arm B (n = 21): mFOLFOX6/Placebo, No. (%) | P |
|---|---|---|---|
| Neutropenia | 12 (28) | 4 (19) | .55 |
| Fatigue | 4 (9) | 1 (5) | 1.0 |
| Peripheral neuropathy | 3 (7) | 2 (10) | 1.0 |
| Gastrointestinala | 3 (7) | 1 (5) | 1.0 |
| Anorexia | 3 (7) | 0 (0) | .55 |
| Nausea/vomiting | 2 (5) | 1 (5) | 1.0 |
| Hoarseness | 2 (5) | 0 (0) | 1.0 |
| Pain/malaise | 2 (5) | 0 (0) | 1.0 |
| Infectionb | 1 (2) | 3 (14) | .1 |
| Leukopenia | 1 (2) | 1 (5) | 1.0 |
| Anemia | 1 (2) | 0 (0) | 1.0 |
| Osteomalacia | 1 (2) | 0 (0) | 1.0 |
| Dehydration | 1 (2) | 0 (0) | 1.0 |
| Syncope/hypotension | 0 (0) | 1 (5) | .33 |
| Superior vena cava syndrome | 0 (0) | 1 (5) | .33 |
| Adverse events of special interest | |||
| Hypertension | 22 (51) | 1 (5) | .0002 |
| Bleeding/hemorrhage | 4 (9) | 1 (5) | 1.0 |
| Thromboembolic event/DVT | 4 (9) | 0 (0) | .29 |
| Left ventricular diastolic dysfunction/heart failure | 2 (5) | 0 (0) | 1.0 |
| Gastrointestinal perforationc | 2 (5) | 0 (0) | 1.0 |
| Arrhythmia/sudden death | 1 (2) | 1 (5) | 1.0 |
| Myocardial infarction | 1 (2) | 0 (0) | 1.0 |
Abbreviation: DVT, deep vein thrombosis.
Includes dysphagia, odynophagia, hiccups, and constipation.
Includes febrile neutropenia, preseptal cellulitis, mastoiditis, pneumonia, and sepsis.
Includes bowel perforation and esophageal perforation.
Two deaths due to cerebral hemorrhage and bowel perforation were thought by the treating investigators to probably be drug-related in the mFOLFOX6/ziv-af-libercept cohort. In addition, there were 2 possibly treatment-related deaths, a suspected arrhythmia in the mFOLFOX6/ziv-aflibercept arm and a sudden death in the mFOLFOX6/placebo arm.
Compared with the patients assigned to the mFOLFOX6/placebo arm, patients in the mFOLFOX6/ ziv-aflibercept arm were treated with less oxaliplatin and 5-fluorouracil during the first 12 and 24 weeks of the trial. The mean relative dose intensity, calculated as the ratio of the actual cumulative dose to the protocol-specified cumulative dose over the specified period, was lower in patients receiving mFOLFOX6/ziv-aflibercept for both 5-fluorouracil and oxaliplatin over the first 12 and 24 weeks of the trial (Fig. 3); these differences were all statistically significant.
Figure 3.
Mean chemotherapy relative dose intensity for 5-FU and oxaliplatin over the first 12 and 24 weeks of the trial. The error bars depict the standard error.
DISCUSSION
This randomized phase 2 trial did not demonstrate superiority for mFOLFOX6/ziv-aflibercept over mFOLFOX6/ placebo; the primary objective of the study, improved 6-month PFS, was not met. Similarly, the median PFS, OS, and objective response rate in the mFOLFOX6/ziv-aflibercept arm were not significantly different from those in the mFOLFOX6/placebo arm.
Our results are consistent with randomized trials assessing antiangiogenic therapy in the first-line therapy of advanced gastric and gastroesophageal junction cancer. Two phase 3 studies (AVAGAST and AVATAR) combining bevacizumab with capecitabine/cisplatin, 1 randomized phase 2 trial combining ramucirumab with mFOLFOX6, and 1 phase 3 trial (RAINFALL) combining ramucirumab with capecitabine/5-fluorouracil and cisplatin all failed to demonstrate a survival advantage for antiangiogenic agents in chemotherapy-naive esophagogastric cancer.9–11,15
The lack of efficacy in our trial and other first-line studies stands in contrast to the success of ramucirumab in the second-line setting.6,7,9–11,15 Potential explanations for the disappointing results in our trial include the increased toxicity observed in the mFOLFOX6/ ziv-aflibercept arm and the resultant decreased exposure to mFOLFOX6. There was no significant difference in the rates of subsequent exposure to ramucirumab between the 2 arms. Other possible explanations include drug-specific differences between the angiogenesis inhibitors and differences in the study population of each of the trials. Ramucirumab and apatinib are VEGFR2 inhibitors, whereas ziv-aflibercept is a blocker of multiple VEGF family members (VEGF-A, VEGF-B, and placental growth factor).12 Moreover, the ramucirumab trials REGARD and RAINBOW and the apatinib trial were limited to patients with gastric and gastroesophageal adenocarcinoma6–8; patients with esophageal cancer were excluded from each of these trials. A subgroup analysis in the first-line FOLFOX/ramucirumab trial suggested an increased benefit of FOLFOX/ramucirumab for patients with gastric and gastroesophageal junctional cancer but not for patients with esophageal cancer.15 In our trial, an underpowered subgroup analysis suggested that ziv-aflibercept did not enhance the activity of first-line mFOLFOX6 in patients with gastric and gastroesophageal junctional cancer. Consistent with this, the results of the phase 3 RAINFALL trial demonstrated that first-line ramucirumab combined with capecitabine/5-fluoroura-cil and cisplatin did not improve survival in a popula-tion limited to patients with gastric and gastroesophageal junctional adenocarcinoma.11
Data from this trial suggest that there was increased toxicity in the mFOLFOX6/ziv-aflibercept arm. There were 2 treatment-related deaths due to cerebral hem-orrhage and bowel perforation in the mFOLFOX6/ ziv-aflibercept cohort. Patients in the mFOLFOX6/ ziv-aflibercept arm were more likely to come off the trial for reasons other than progressive disease. In comparison with the mFOLFOX6/placebo arm, there were more patients in the mFOLFOX6/ziv-aflibercept arm who came off the trial for drug-related toxicity, prolonged treatment delays, or treatment-related death. In our study, the addition of ziv-aflibercept to mFOLFOX6 caused a decrease in the relative dose intensity of oxaliplatin and 5-fluorouracil in the first 12 and 24 weeks of trial.
It is difficult to determine whether the increased toxicity that we observed in this trial was primarily related to the treatment population or to ziv-aflibercept. The data from another trial testing angiogenic inhibition (FOLFOX/ramucirumab) in first-line metastatic esoph-agogastric cancer also indicated a greater frequency of treatment discontinuations for reasons other than progressive disease.15 Ziv-aflibercept has been associated with a clinically significant increase in toxicity in other cancers such as small cell lung cancer and prostate cancer.16–18 A trial evaluating a combination of ziv-aflibercept, cisplatin, and pemetrexed in non–small cell lung cancer was closed prematurely because of toxicity.17 However, in colon cancer, when it was combined with both FOLFOX and FOLFIRI, the toxicity pattern was comparable to those of other antiangiogenic agents used in colon cancer.13,19
The OS and objective response rates observed in both arms of the study compare favorably with those observed in other first-line trials in metastatic gastroesophageal cancer.3,15 Because of the relatively small size of our trial, it is difficult to draw meaningful conclusions about this. However, it is noteworthy that 44% of the patients in our trial received at least 3 lines of therapy, with 50% receiving ramucirumab and 19% receiving PD1-directed therapy.
In conclusion, the use of ziv-aflibercept did not improve the efficacy of first-line mFOLFOX6 in metastatic esophagogastric cancer and was associated with a higher level of toxicity. Further study of ziv-aflibercept in a non-molecularly defined population of esophagogastric cancers is not warranted.
Acknowledgments
FUNDING SUPPORT
This trial was supported by Sanofi-Aventis. The work was also supported by a grant from the National Institutes of Health (P50CA127003). The work of Rakesh K. Jain, Dan G. Duda, and Yves Boucher is supported by National Institutes of Health grant P01CA080124.
James M. Cleary has received research funding from Merck and Tesaro; is a consultant to Bristol-Myers Squibb; and has received travel funding from Bristol-Myers Squibb, Agios, and Roche. Thomas A. Abrams has received honoraria from Merck, Bristol-Myers Squibb, Exelixis, Bayer, Sirtex, and Celgene; has served as a consultant to Aduro Biotech; has received research funding from Lilly and Celgene; has received travel funding from Lilly; and has received personal fees from Kaleido, Ipsen, Eisai, and Genentech. Matthew B. Yurgelun has received research funding from Myriad Genetics. Gabriel A. Brooks reports consulting payments from CareCentrix. Jennifer A. Chan has stock ownership in Merck; has received honoraria from Ipsen; is a consultant to Novartis, Ipsen, Advanced Acceleration Applications, and Exelixis; has received clinical trial support (institutional) from Novartis and Tarveda and research support (institutional) from Ipsen; has received personal fees from Lexicon; and has received research funding from Sanofi and Lilly. Lawrence S. Blaszkowsky has a family member with stock in Pfizer. Lipika Goyal has received travel funding from Taiho Oncology and Debiopharm. Jeffrey A. Meyerhardt reports personal fees from Array Pharmaceutical, Ignyta, and Cota Healthcare. Kimmie Ng reports grants and nonfinancial support from Pharmavite; personal fees from Genentech, Bayer, Seattle Genetics, and Lilly; grants from Gilead Sciences, Celgene, and Trovagene; and grants and personal fees from Tarrex Biopharma. Diane M. F. Savarese is employed by Wolters Kluwer/UpToDate. Yves Boucher reports personal fees from XTuit; in addition, Boucher has a patent with royalties paid to XTuit. Dan G. Duda has received honoraria from Bristol-Myers Squibb; consultancy fees from Bayer, Tilos, and twoXAR; and research funding from Merrimack, Leap Therapeutics, Bayer, Bristol-Myers Squibb, and Exelixis. Rakesh K. Jain has been issued a patent on antihypertension agents for cancer therapy; has received honoraria from Amgen; has received consultancy fees from Merck, Ophthotech, Pfizer, SPARC, and SynDevRx; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; and serves on the board of directors of XTuit and the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, the Tekla Healthcare Opportunities Fund, and the Tekla World Healthcare Fund. Dr. Fuchs reports consulting role for Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. Dr. Fuchs also serves as a Director for CytomX therapeutics and owns unexercised stock options for CytomX. Peter C. Enzinger is a consultant for and has received hono-raria from Merck, Lilly, Celgene, Astellas Oncology, Loxo Oncology, Five Prime, and Taiho Oncology.
Footnotes
CONFLICT OF INTEREST DISCLOSURES
The other authors made no disclosures.
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