Patients who received FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept had a median progression-free survival of 4.9 months. |
FOLFIRI plus aflibercept after trifluridine/tipiracil plus bevacizumab did not improve survival in patients with metastatic colorectal cancer. |
However, some angiogenic biomarkers tended to be correlated with better efficacy of FOLFIRI plus aflibercept, and FOLFIRI plus aflibercept may be effective regardless of the levels of placental growth factor. |
1 Introduction
2 Patients and Methods
2.1 Study Design
2.2 Patients
2.3 Treatment Procedures
2.4 Responses and Adverse Events
2.5 Endpoints
2.6 Biomarker Analyses
2.7 Statistical Analysis
3 Results
3.1 Patient Characteristics
Characteristics | Categories | No. of patients (%) |
---|---|---|
Age | Median years (range) | 68 (47–80) |
Sex | Male | 10 (38%) |
Female | 16 (62%) | |
ECOG PS | 0 | 11 (42%) |
1 | 15 (58%) | |
Primary tumor locationa | Right | 8 (31%) |
Left | 18 (69%) | |
Tumor differentiation | Well, moderate | 22 (85%) |
Por, Muc, Sig | 4 (15%) | |
Primary tumor resection | Yes | 23 (88%) |
No | 3 (12%) | |
RAS status | Mutant | 12 (46%) |
Wild type | 14 (54%) | |
BRAF status | V600E mutant | 2 (8%) |
Wild type | 12 (46%) | |
Unknown | 12 (46%) | |
Microsatellite instability | Stable | 14 (54%) |
Unknown | 12 (46%) | |
Metastatic sites | Liver | 17 (65%) |
Lung | 18 (69%) | |
Lymph node | 8 (31%) | |
Peritoneum | 7 (27%) | |
Bone | 1 (4%) | |
Number of metastatic sites | 0–1 | 8 (31%) |
≥ 2 | 18 (69%) | |
Prior systemic agents | Fluoropyrimidine | 26 (100%) |
Trifluridine/tipiracil | 26 (100%) | |
Oxaliplatin | 26 (100%) | |
Bevacizumab | 26 (100%) | |
Anti-EGFR mAb | 6 (23%) | |
Time from initial treatment for metastatic disease to enrollment in this study. | Median months (range) | 21 (9.6–75) |
3.2 Efficacy
Response | No. of patients (%) |
---|---|
Complete response | 0 (0) |
Partial response | 2 (8) |
Stable disease | 14 (54) |
Progressive disease | 9 (35) |
Non-evaluable | 1 (4) |
Overall response rate | 8% (95% CI 0.9–25) |
Disease control rate | 62% (95% CI 41–80) |
3.3 Safety
Adverse event | No. of patients (%) | |
---|---|---|
All grades | > Grade 3 | |
Hematologic | ||
Neutropenia | 21 (81) | 18 (69) |
WBC count decreased | 19 (73) | 7 (27) |
Anemia | 14 (54) | 5 (19) |
Platelet count decreased | 8 (31) | 1 (4) |
Nonhematologic | ||
Proteinuria | 18 (69) | 1 (4) |
Appetite loss | 17 (65) | 3 (12) |
Fatigue | 16 (62) | 5 (19) |
Stomatitis | 14 (54) | 1 (4) |
AST elevation | 14 (54) | 0 (0) |
Alopecia | 13 (50) | – |
Diarrhea | 11 (42) | 0 (0) |
Hypertension | 10 (39) | 3 (12) |
Nausea | 9 (35) | 1 (4) |
Vomiting | 5 (19) | 0 (0) |
Infection | 5 (19) | 0 (0) |
Dysgeusia | 4 (15) | 0 (0) |
Hemorrhage | 2 (8) | 0 (0) |
Thromboembolism | 1 (4) | 1 (4) |
Respiratory failure | 1 (4) | 1 (4) |
3.4 Biomarker Analyses
Factors (median pg/mL) | No. of patients | PFS months (95% CI) | HR (95% CI) P-value | OS months (95% CI) | HR (95% CI) P-value |
---|---|---|---|---|---|
Ang-2 (1100) | |||||
Low | 11 | 9.0 (2.4–11.2) | 0.47 (0.20–1.09) 0.07 | 14.9 (9.3–23.6) | 0.51 (0.19–1.38) 0.18 |
High | 14 | 2.9 (1.8–5.1) | 11.5 (5.1–17.3) | ||
HGF (160) | |||||
Low | 12 | 5.2 (1.8–9.0) | 1.32 (0.58–3.01) 0.51 | 13.4 (5.1–23.6)) | 0.66 (0.31–2.12) 0.66 |
High | 13 | 4.0 (2.2–9.2) | 10.7 (7.9–17.3) | ||
PlGF (16) | |||||
Low | 12 | 5.4 (1.8–11.2) | 0.84 (0.37–1.89) 0.67 | 14.5 (6.6–23.6) | 0.65 (0.25–1.72) 0.64 |
High | 13 | 4.0 (2.0–7.0) | 10.7 (5.1–17.3) | ||
VEGF-D (192) | |||||
Low | 12 | 5.8 (1.8–11.2) | 0.75 (0.33–1.71) 0.49 | 12.0 (7.9–23.6) | 0.84 (0.32–2.18) 0.71 |
High | 13 | 4.0 (2.0–5.4) | 14.5 (5.5–17.3) | ||
OPN (14000) | |||||
Low | 12 | 5.4 (1.8–11.70 | 0.41 (0.16–1.05) 0.05 | 13.3 (5.1–23.6) | 1.02 (0.39–2.65) 0.97 |
High | 13 | 3.3 (2.0–5.4) | 14.6 (7.9–NE) | ||
NRP-1 (182000) | |||||
Low | 12 | 3.8 (1.8–11.2) | 1.12 (0.50–2.52) 0.78 | 13.3 (4.9–23.6) | 1.15 (0.44–3.30) 0.77 |
High | 13 | 4.6 (2.4–9.0) | 14.5 (7.9–NE) | ||
VEGFR2 (5320) | |||||
Low | 12 | 2.6 (1.8–9.2) | 1.36 (0.61–3.04) 0.45 | 11.2 (4.9–14.9) | 1.69 (0.66–4.40) 0.28 |
High | 13 | 5.1 (2.4–9.0) | 13.4 (9.6–NE) | ||
IL-8 (6) | |||||
Low | 12 | 7.2 (1.8–11.2) | 0.68 (0.30–1.55) 0.35 | 14.8 (9.3–23.6) | 0.58 (0.22–1.52) 0.26 |
High | 13 | 3.3 (2.0–5.3) | 9.6 (5.1–NE) | ||
TIMP-1 (254000) | |||||
Low | 12 | 6.2 (1.8–11.2) | 0.49 (0.21–1.16) 0.10 | 14.9 (7.8–23.6) | 0.51 (0.19–1.36) 0.17 |
High | 13 | 3.3 (2.0–5.3) | 10.5 (5.1–14.6) | ||
TSP-2 (5760) | |||||
Low | 12 | 2.6 (1.8–11.2) | 1.14 (0.50–2.57) 0.76 | 13.4 (5.5–23.6) | 0.73 (0.28–1.93) 0.53 |
High | 13 | 5.1 (2.4–7.0) | 10.7 (6.6–17.3) | ||
sICAM-1 (26900) | |||||
Low | 12 | 4.7 (1.8–9.3) | 0.77 (0.34–1.77) 0.54 | 12.0 (7.82–NE) | 1.18 (0.45–3.08) 0.73 |
High | 13 | 4.6 (2.0–9.0) | 14.6 (5.5–23.6) | ||
sVCAM-1 (1140000) | |||||
Low | 12 | 5.4 (1.8–9.3) | 1.04 (0.47–2.43) 0.91 | 13.3 (4.9–23.6) | 1.28 (0.49–3.34) 0.61 |
High | 13 | 4.0 (2.4–9.0) | 14.9 (7.8–NE) |