Abstract
This phase II trial examined the addition of ramucirumab, a vascular endothelial growth factor receptor-2 monoclonal antibody, to mFOLFOX6 as front-line therapy for patients with advanced gastric/GEJ or esophageal adenocarcinoma. A survival benefit was not observed in the ITT population, but an exploratory analysis suggested a potential benefit for ramucirumab in the gastric/GEJ cancer subgroup.
Background
We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).
Patients and methods
Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure–response analysis was undertaken.
Results
Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69–1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure–response analysis indicated that patients with higher ramucirumab exposure had longer OS.
Conclusion
The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.
Clinicaltrials.gov identifier
Key words: gastroesophageal junction, gastric cancer, esophageal cancer, ramucirumab, vascular endothelial growth factor
introduction
Platinum-/fluoropyrimidine (FP)-based combinations are acceptable first-line drug regimens for the treatment of advanced adenocarcinoma of the esophagus, gastroesophageal junction (GEJ), or gastric cardia, but confer a poor progression-free survival (PFS) and overall survival (OS) [1, 2]. The challenge of improving upon standard first-line therapy is highlighted by recently reported negative results from trials examining agents targeting the epidermal growth factor receptor [3] or MET pathway [4].
Ramucirumab is a recombinant human anti-vascular endothelial growth factor receptor-2 monoclonal antibody (mAb) that prevents ligand binding and receptor-mediated pathway activation in endothelial cells. Ramucirumab was shown to improve OS in patients with previously treated advanced gastric/GEJ adenocarcinoma, but has not been tested in the first-line setting [5, 6].
We report the primary results from the first randomized trial evaluating ramucirumab, in combination with 5-fluorouracil (5-FU) and oxaliplatin, in primarily Caucasian US patients with previously untreated advanced esophagogastric adenocarcinoma.
methods
study design and patients
This randomized, placebo-controlled, double-blind Phase II trial included patients with metastatic or non-resectable, locally advanced adenocarcinoma of the esophagus, GEJ, or stomach with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Exclusion criteria included any arterial thromboembolic event within 6 months before randomization, active bleeding within 14 days before randomization, Grade 3/4 gastrointestinal bleeding within 3 months before randomization, or poorly controlled hypertension. See supplementary Material, available at Annals of Oncology online.
Supplementary Data.
treatment
Patients were randomly assigned 1:1 to receive ramucirumab [8 mg/kg intravenously (IV) every 2 weeks] or placebo, followed by modified FOLFOX6 (mFOLFOX6; both arms) on Day 1 of each cycle (14-day treatment cycle). Oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2) were administered IV, followed by 5-FU as an IV bolus (400 mg/m2) and continuous IV over 46–48 h (2400 mg/m2). Patients were treated until radiographic or symptomatic progressive disease (PD), toxicity requiring cessation, withdrawal of consent, or other withdrawal criteria were met. If one of the regimen components was discontinued due to toxicity, treatment was continued with the remaining components if clinically indicated (see supplementary Material, available at Annals of Oncology online).
assessments
Baseline disease assessment was taken within 21 days before randomization, and then every 8 weeks (±7 days) until PD using RECIST v.1.1. See supplementary Material, available at Annals of Oncology online.
pharmacokinetic analysis
Blood samples for the determination of serum ramucirumab concentrations were collected before Cycles 1, 4, 8, 12, 16, and at 30-day follow-up. Samples were analyzed for ramucirumab using a validated enzyme-linked immunosorbent assay method at Intertek Pharmaceutical Services (San Diego, CA).
statistical analyses
The trial was designed with a planned enrollment of 166 patients, with an assumption of 125 PFS events, and with 80% power to detect a hazard ratio (HR) for a PFS of 0.71 (median 5.8 versus 8.1 months for placebo versus ramucirumab arms, respectively; one-sided alpha = 0.15) [2]. A stratified log-rank test was used to assess PFS in the intent-to-treat (ITT) population. PFS was defined as the time from randomization to first-documented objective PD or any-cause death, whichever came first, with censoring at last adequate radiological assessment. PFS after censoring for premature treatment discontinuation was defined the same as PFS, except with censoring at the time of treatment discontinuation for reasons other than PD or death. The Kaplan–Meier method was used to estimate survival curves. Hazard ratios were estimated with stratified Cox proportional hazards models. See supplementary Material, available at Annals of Oncology online.
Population pharmacokinetic (PopPK) analyses were conducted as previously described [7]. The PopPK-predicted minimum concentration following the first dose (Cmin,1) was used to evaluate the relationship between ramucirumab exposure and measurements of clinical outcomes. Patients with available ramucirumab concentration data were grouped into low and high Cmin,1 groups (dichotomized by the median). The HR for each group versus the control arm was estimated using a univariate Cox model.
results
patients
Between April 2011 and August 2012, 84 patients were enrolled in each arm (Figure 1) across the USA (supplementary Table S1, available at Annals of Oncology online). All patients were included in efficacy analyses. The safety analysis included 82 patients (98%) in the ramucirumab plus mFOLFOX6 (ramucirumab) arm and 80 patients (95%) in the placebo plus mFOLFOX6 (placebo) arm who received at least one dose of study drug.
Figure 1.
CONSORT diagram. ITT, intent to treat.
Supplementary Data.
Baseline characteristics were generally balanced between arms (Table 1). Almost half of the patients had adenocarcinomas arising from the esophagus.
Table 1.
Baseline patient demographics and clinical characteristics
| Characteristics | RAM + mFOLFOX6 (n = 84) No. (%) |
PBO + mFOLFOX6 (n = 84) No. (%) |
|---|---|---|
| Age, years | ||
| Median (range) | 64.5 (27–83) | 60 (34–82) |
| <65 | 42 (50.0) | 56 (66.7) |
| ≥65 | 42 (50.0) | 28 (33.3) |
| Male | 63 (75.0) | 61 (72.6) |
| Race | ||
| White | 77 (91.7) | 76 (90.5) |
| Black or African American | 3 (3.6) | 3 (3.6) |
| Asian | 2 (2.4) | 4 (4.8) |
| Native Hawaiian or other Pacific islander | 2 (2.4) | 1 (1.2) |
| ECOG PSa | ||
| 0 | 40 (47.6) | 43 (51.2) |
| 1 | 43 (51.2) | 41 (48.8) |
| Type of cancer | ||
| Esophagus | 39 (46.4) | 41 (48.8) |
| GEJ | 26 (31.0) | 23 (27.4) |
| Gastric | 19 (22.6) | 20 (23.8) |
| Disease extent | ||
| Locally advanced (Stages IIB–IIIC) | 4 (4.8) | 5 (6.0) |
| Metastatic (Stage IV) | 80 (95.2) | 79 (94.0) |
| Median duration of disease, months (range) | 1.33 (0.5–176.0) | 1.12 (0.4–46.0) |
| Measurable disease | 67 (79.8) | 70 (83.3) |
| Weight loss over 3 monthsb | ||
| <10% | 54 (64.3) | 54 (64.3) |
| ≥10% | 26 (31.0) | 29 (34.5) |
ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; n, number of patients in group; PBO, placebo; RAM, ramucirumab.
One patient missing in the RAM + mFOLFOX6 arm.
Four patients missing in the RAM + mFOLFOX6 arm and one patient in the PBO + mFOLFOX6 arm.
efficacy
Median PFS (6.4 versus 6.7 months; stratified HR 0.98; 95% CI 0.69–1.37; P = 0.886) and OS (11.7 versus 11.5 months; stratified HR 1.08; 95% CI 0.73–1.58; P = 0.712) in the ITT population were not different between treatment arms (Table 2 and Figure 2). Figure 3A shows the effect of ramucirumab plus mFOLFOX6 across exploratory subgroups. Objective response rates (45.2% versus 46.4%) were similar between arms (Table 2). The best overall response of stable disease (39.3% versus 20.2%) favored the ramucirumab arm. The median duration of response was 7.4 months in the ramucirumab arm and 5.8 months in the placebo arm (P = 0.908).
Table 2.
Clinical responses
| Efficacy variable | RAM + mFOLFOX6 (n = 84) |
PBO + mFOLFOX6 (n = 84) |
P value |
|---|---|---|---|
| Median PFS, months | 6.4 | 6.7 | |
| HR (95% CI) | 0.98 (0.69–1.37) | 0.886 | |
| 3-Month PFS, % (95% CI) | 89.0 (80.0–94.1) | 75.3 (64.4–83.3) | 0.020 |
| 6-Month PFS, % (95% CI) | 55.3 (43.8–65.4) | 54.3 (42.9–64.4) | 0.901 |
| 9-Month PFS, % (95% CI) | 40.2 (29.5–50.7) | 35.4 (25.1–45.8) | 0.529 |
| 12-Month PFS, % (95% CI) | 23.3 (14.6–33.1) | 26.2 (17.0–36.2) | 0.677 |
| Median OS, months | 11.7 | 11.5 | |
| HR (95% CI) | 1.08 (0.73–1.58) | 0.712 | |
| Median TTP, months | 8.7 | 7.1 | |
| HR (95% CI) | 0.88 (0.59–1.30) | 0.516 | |
| Median duration of response, months | 7.4 | 5.8 | |
| HR (95% CI) | 1.03 (0.62–1.71) | 0.908 | |
| Best response, n (%) | |||
| Complete response (CR) | 6 (7.1) | 5 (6.0) | |
| Partial response (PR) | 32 (38.1) | 34 (40.5) | |
| Stable disease (SD) | 33 (39.3) | 17 (20.2) | |
| Progressive disease | 6 (7.1) | 18 (21.4) | |
| Not done | 7 (8.3) | 10 (11.9) | |
| Objective response (CR + PR), n (%) (95% CI) |
38 (45.2) (34.3–56.5) |
39 (46.4) (35.5–57.6) |
0.830 |
| Disease control (CR + PR + SD), n (%) (95% CI) |
71 (84.5) (75.0–91.5) |
56 (66.7) (55.5–76.6) |
0.008 |
CI, confidence interval; HR, hazard ratio; n, number of patients in group; OS, overall survival; PBO, placebo; PFS, progression-free survival; RAM, ramucirumab; TTP, time to progression.
Figure 2.
The Kaplan–Meier analysis of efficacy in the intent-to-treat (ITT) population. Progression-free survival (A) and overall survival (B).
Figure 3.
Forest plot for subgroup analysis of progression-free survival (PFS) in the ITT population with and without censoring for premature treatment discontinuation. PFS in the ITT population (A) and PFS in the ITT population after censoring for premature treatment discontinuation (B). CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; HR, hazard ratio; ITT, intent to treat; PBO, placebo; RAM, ramucirumab.
safety
Most Grade ≥3 toxicities did not differ significantly between arms (Table 3). The most common all-cause Grade ≥3 treatment-emergent adverse events (TEAEs) in ramucirumab versus placebo arms were neutropenia (26.8% versus 36.3%), fatigue (18.3% versus 15.0%), and hypertension (15.9% versus 3.8%). A few FOLFOX-related Grade ≥3 toxicities were slightly more common in the ramucirumab arm, as was ramucirumab-related hypertension (Table 3). Although Grade 1 and 2 bleeding (mostly epistaxis) was numerically more frequent in the ramucirumab arm, the frequency of Grade ≥3 bleeding was similar between arms. There were no Grade 4 or 5 bleeding events in the ramucirumab arm.
Table 3.
TEAEs by the worst grade (safety population)
| TEAEsa |
RAM + mFOLFOX6 (n = 82), No. (%) |
PBO + mFOLFOX6 (n = 80), No. (%) |
||||
|---|---|---|---|---|---|---|
| Any | Grade 1–2 | Grade ≥3 | Any | Grade 1–2 | Grade ≥3 | |
| Any TEAE | 82 (100.0) | 8 (9.8) | 74 (90.2) | 80 (100.0) | 13 (16.3) | 67 (83.8) |
| Fatigueb | 55 (67.1) | 40 (48.8) | 15 (18.3) | 58 (72.5) | 46 (57.5) | 12 (15.0) |
| Nausea | 52 (63.4) | 44 (53.7) | 8 (9.8) | 54 (67.5) | 52 (65.0) | 2 (2.5) |
| Neuropathyb | 53 (64.6) | 46 (56.1) | 7 (8.5) | 55 (68.8) | 46 (57.5) | 9 (11.3) |
| Thrombocytopeniab | 46 (56.1) | 41 (50.0) | 5 (6.1) | 31 (38.8) | 29 (36.3) | 2 (2.5) |
| Neutropeniab | 45 (54.9) | 23 (28.0) | 22 (26.8) | 41 (51.3) | 12 (15.0) | 29 (36.3) |
| Constipation | 37 (45.1) | 36 (43.9) | 1 (1.2) | 32 (40.0) | 31 (38.8) | 1 (1.3) |
| Diarrhea | 36 (43.9) | 28 (34.1) | 8 (9.8) | 33 (41.3) | 28 (35.0) | 5 (6.3) |
| Decreased appetite | 34 (41.5) | 29 (35.4) | 5 (6.1) | 22 (27.5) | 22 (27.5) | 0 (0.0) |
| Weight decreased | 28 (34.1) | 27 (32.9) | 1 (1.2) | 21 (26.3) | 20 (25.0) | 1 (1.3) |
| Peripheral edema | 21 (25.6) | 20 (24.4) | 1 (1.2) | 16 (20.0) | 15 (18.8) | 1 (1.3) |
| Epistaxis | 24 (29.3) | 24 (29.3) | 0 (0.0) | 8 (10.0) | 8 (10.0) | 0 (0.0) |
| Dehydration | 23 (28.0) | 16 (19.5) | 7 (8.5) | 12 (15.0) | 11 (13.8) | 1 (1.3) |
| Dizziness | 19 (23.2) | 18 (22.0) | 1 (1.2) | 12 (15.0) | 12 (15.0) | 0 (0.0) |
| Headacheb | 19 (23.2) | 17 (20.7) | 2 (2.4) | 12 (15.0) | 12 (15.0) | 0 (0.0) |
| Mucosal inflammation | 17 (20.7) | 15 (18.3) | 2 (2.4) | 9 (11.3) | 8 (10.0) | 1 (1.3) |
| Hypokalemiab | 16 (19.5) | 11 (13.4) | 5 (6.1) | 7 (8.8) | 5 (6.3) | 2 (2.5) |
| Deep vein thrombosis | 9 (11.0) | 7 (8.5) | 2 (2.4) | 4 (5.0) | 4 (5.0) | 0 (0.0) |
| Adverse events of special interest | ||||||
| Bleeding/hemorrhagec | 36 (43.9) | 31 (37.8) | 5 (6.1) | 20 (25.0) | 15 (18.8) | 5 (6.3) |
| Epistaxis | 24 (29.3) | 24 (29.3) | 0 (0.0) | 8 (10.0) | 8 (10.0) | 0 (0.0) |
| GI hemorrhage eventsd | 10 (12.2) | 5 (6.1) | 5 (6.1) | 5 (6.3) | 1 (1.3) | 4 (5.0) |
| Hypertension | 31 (37.8) | 18 (22.0) | 13 (15.9) | 10 (12.5) | 7 (8.8) | 3 (3.8) |
| VTEe | 13 (15.9) | 10 (12.2) | 3 (3.7) | 13 (16.3) | 9 (11.3) | 4 (5.0) |
| ATEf | 3 (3.7) | 1 (1.2) | 2 (2.4) | 1 (1.3) | 1 (1.3) | 0 (0.0) |
| Renal failure | 5 (6.1) | 5 (6.1) | 0 (0.0) | 3 (3.8) | 2 (2.5) | 1 (1.3) |
Note: There was one GI perforation (gastric, Grade 4) in the RAM arm and none in the PBO arm.
aTEAEs are shown for which consolidated or preferred terms were >10% any grade in the RAM arm and higher in RAM by an absolute difference of >5%; or >5% Grade ≥3 and higher in RAM; or selected preferred terms of high interest (neuropathy, neutropenia, VTE, ATE, and renal failure).
bConsolidated terms.
cFor bleeding (all types), there were no Grade 5 events. The most common type of bleeding is shown.
dTypes of Grade 3 GI bleed were gastric (n = 2 in RAM versus 0 in PBO), GI bleed NOS (3 versus 1), small intestinal (0 versus 1), and upper GI (0 versus 1). There was one Grade 4 GI bleed NOS (PBO) event, and one Grade 3 anastomotic ulcer (PBO).
eFor VTE, there was one Grade 4 event (venous embolism in PBO arm). Grade 3 events were deep vein thrombosis (2 versus 0) and pulmonary embolism (2 versus 2), and a Grade 3 embolism (PBO).
fFor ATE, there were two Grade 3 events (coronary spasm, myocardial infarction; 2 versus 0) in RAM, and no Grade ≥4 events.
ATE, arterial thromboembolic events; GI, gastrointestinal; n, number of patients in group; NOS, not otherwise specified; PBO, placebo; RAM, ramucirumab; TEAE, treatment-emergent adverse event; VTE, venous thromboembolic events.
treatment duration
Discontinuation of study treatment for reasons other than PD was more common in the ramucirumab versus placebo arm (48% versus 16%). Reasons for treatment discontinuation were PD (43% ramucirumab arm versus 69% placebo arm), patient or investigator decision (27% versus 10%), AEs (21% versus 6%), or death (1% versus 4%).
The median number of infusions received for ramucirumab/placebo, 5-FU, oxaliplatin, and leucovorin was 9 for each treatment in the ramucirumab arm and 11, 11, 10, and 11, respectively, in the placebo arm (supplementary Table S2, available at Annals of Oncology online). After discontinuing study treatment, the percentage of patients receiving systemic anti-cancer therapy was 48.8% and 36.9% in the ramucirumab and placebo arms, respectively (supplementary Table S3, available at Annals of Oncology online).
Supplementary Data.
Supplementary Data.
exploratory analyses
Given the high rate of premature treatment discontinuation in the ramucirumab arm, we conducted a post hoc exploratory analysis censored for treatment discontinuation for reasons other than PD, similar to a previously used approach [8]. The HR for PFS favored the ramucirumab arm in the ITT population (HR 0.76; 95% CI 0.50–1.15; P = 0.194) (Figure 3B). In two preplanned subgroup analyses (see supplementary Material, available at Annals of Oncology online), the HR for PFS favored the ramucirumab arm in the gastric/GEJ cancer subgroup (n = 88; median 9.3 versus 7.6 months; HR 0.53; 95% CI 0.29–0.97; P = 0.036), but not in the esophageal cancer subgroup (n = 80; median 5.8 versus 5.8 months; HR 1.10; 95% CI 0.61–1.97; P = 0.746; interaction P = 0.054; Figure 3B; supplementary Figure S1A–D, available at Annals of Oncology online).
Supplementary Data.
The PopPK-estimated Cmin,1 for patients in the ramucirumab arm with available PK data (n = 71) was 34.5 µg/ml (range 13.6–72.3 µg/ml). Patients in the ramucirumab arm were dichotomized by median Cmin,1. In the ITT population, a higher ramucirumab concentration was associated with longer OS compared with patients in the placebo arm, but not with prolonged PFS (supplementary Figure S1E and F, available at Annals of Oncology online).
discussion
In this randomized Phase II trial examining the addition of ramucirumab to mFOLFOX6, an improvement in PFS or OS was not observed in the ITT population. These findings contrast with the results from two Phase III second-line trials in which the addition of ramucirumab to paclitaxel (RAINBOW) or to best supportive care (REGARD) improved PFS and OS [5, 6]. Several factors may have contributed to the different results among studies.
First, disease biology could differ between populations of patients in the first- and second-line settings. Our data are consistent with negative results from the ITT population of prior randomized trials that added bevacizumab or aflibercept to first-line platinum plus FP [9., 10., 11.].
Second, a higher rate of premature discontinuation was observed in the ramucirumab arm. The study design allowed for treatment until PD, as well as the discontinuation of either oxaliplatin, FP, or both while continuing ramucirumab or placebo [1., 2., 3., 5, 6, 12., 13., 14.]. The reasons for stopping treatment with ramucirumab or chemotherapy before PD are not clear and did not implicate a specific AE. This raises the possibility that the addition of ramucirumab to mFOLFOX6 led to increased toxicity (mostly low grade). However, the role of chance cannot be excluded.
Decreased appetite, dehydration, and Grade ≥3 nausea were some of the most frequently reported non-hematologic TEAEs in both groups and were more common in the ramucirumab arm. These events are common in patients with gastric/GEJ cancer; incidences reported in our trial are in the range of those previously reported in large Phase III gastric cancer trials [2, 3, 5]. As expected, hypertension and bleeding (mainly Grade 1–2 epistaxis) were more common in the ramucirumab arm. No new ramucirumab-related safety signals were identified.
Third, our study population had a high proportion of patients (almost half) whose adenocarcinoma originated in the esophagus in contrast to RAINBOW [5], REGARD [6], and trials examining bevacizumab (AVAGAST, AVATAR) [9, 10], in which eligibility was restricted to gastric/GEJ tumors. Although our exploratory analysis suggested a potential benefit for ramucirumab in the gastric/GEJ cancer subgroup and some data suggest that biologic differences may exist between esophageal versus gastric/GEJ cancer (see supplementary Material, available at Annals of Oncology online), these data should be interpreted as hypothesis-generating. Of note, a smaller randomized Phase II trial (N = 64), in which 41% of patient tumors were esophageal, recently reported negative results for the addition of aflibercept to FOLFOX [11].
Fourth, the chemotherapy backbone was FOLFOX, in contrast to paclitaxel (RAINBOW [5]) or no chemotherapy (REGARD [6]). In our trial, the addition of ramucirumab to mFOLFOX6 did not enhance the ORR, whereas the ORR was improved when ramucirumab was added to paclitaxel in RAINBOW (27% versus 16%) [5] or when bevacizumab was added to cisplatin/FP in AVAGAST (46% versus 37%) [10]. These data suggest that, in gastric/GEJ cancers, anti-angiogenesis therapy may be more effective when combined with a taxane or cisplatin than when combined with oxaliplatin-based therapies. However, this question remains unresolved.
We found that patients with a high ramucirumab Cmin,1 appeared to have a longer OS than patients with a lower level of Cmin,1 or those who received placebo. An exposure–response relationship for ramucirumab was also observed in REGARD and RAINBOW, in which a higher exposure to ramucirumab was associated with longer PFS and OS [15]. Although the small sample size of this study limits analysis of ramucirumab Cmin,1 in association with covariates, a PopPK meta-analysis across 11 other ramucirumab studies did not identify any significant covariates [7]. Exposure–response relationships have been observed for other mAbs or antibody–drug conjugates, including ipilimumab [16], trastuzumab [17], and ado-trastuzumab emtansine [18]. In contrast to REGARD/RAINBOW, the current study did not find an association between Cmin,1 and PFS. Although a smaller sample size may account for this difference, further research is necessary, and the current data should be regarded as hypothesis-generating.
Our findings have relevance for further development of this agent. A new front-line Phase III trial (RAINFALL; ClinicalTrials.gov identifier: NCT02314117) examines ramucirumab in gastric/GEJ adenocarcinoma combined with different chemotherapy (cisplatin/FP), using more frequent dosing of ramucirumab and excluding tumors arising from the esophagus.
funding
This work was supported by Eli Lilly and Company.
disclosure
HHY reports honoraria from Eli Lilly and Company and Five Prime Therapeutics; consulting or advisory fees from Eli Lilly and Company and Five Prime Therapeutics; research funding from Roche-Genentech, Merck, and Eli Lilly and Company; and travel, accommodations, or expenses from Eli Lilly and Company. PAP reports honoraria from Celgene, Amgen, Roche, Sanofi, Bayer, Bristol-Myers Squibb, Novartis, Ipsen, Halozyme Therapeutics, and Merrimack Pharmaceuticals; consulting or advisory fees from Celgene, Novartis, Halozyme, Merrimack Pharmaceuticals, Gilead Sciences, and Ipsen; speakers' bureau fees from Celgene, Bayer, Amgen, Roche, and Sanofi; and research funding from Bayer, Incyte, Karyopharm Therapeutics, Merck, Taiho Pharmaceutical, Momenta Pharmaceuticals, Novartis, Plexxikon, Immunomedics, Regeneron Pharmaceuticals, and Genentech. ALC reports honoraria from Celgene, Onyx Pharmaceuticals, and Sanofi and speakers' bureau fees from Celgene, Sanofi, and Eli Lilly and Company. NL is an employee at and owns stock in Novartis. JDS is an employee at Rocket Pharmaceuticals, owns stock in Eli Lilly and Company, and was an employee at Eli Lilly and Company during the conduct of the study. LG, YH, YX, and DF are all employed with and own stock in Eli Lilly and Company. YH additionally reports patents, royalties, and other intellectual property fees from Eli Lilly and Company. SRA reports travel, accommodations, or expenses from IBM. ZAW reports consulting or advisory role fees from Taiho Pharmaceutical and Sirtex; speakers' bureau fees from Genentech; research funding from Novartis, Plexxikon, Pfizer, and BioMarin Pharmaceutical; and travel, accommodations, or expenses from Genentech and Eli Lilly and Company. All remaining authors have declared no conflicts of interest.
Supplementary Material
acknowledgements
We would like to thank the patients, investigators, and institutions involved in this study. Medical writing assistance and editorial support were provided by Andrea Humphries, PhD, and Noelle Gasco of inVentiv Health Clinical and were funded by Eli Lilly and Company. We would also like to thank Minori Koshiji, the clinical research physician who was involved with the study while an employee of Eli Lilly, Bridgewater, NJ.
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