Table 3.
Bevacizumab trials.
| Trial | Phase | Treatment Arms | Setting | Results | Safety/Toxicity Grade (G) | References |
|---|---|---|---|---|---|---|
| Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer |
III | Irinotecan, bolus fluorouracil, and leucovorin (IFL) + bevacizumab vs.1 IFL + placebo | First line | Primary endpoint: OS2 -mOS3: 20.3 months in IFL + bevacizumab group vs. 15.6 months in IFL + placebo group (HR4=0.66; p < 0.001) -mPFS5: 10.6 months in IFL+ bevacizumab vs. 6.2 months in IFL + placebo (HR=0.54; p < 0.001) -RR6: 44.8% vs. 34.8% (p = 0.004)-median duration of the response 10.4 months with IFL+ bevacizumab vs. 7.1 months with IFL + placebo (HR=0.62; p = 0.001) |
G3 hypertension: 11.0% with IFL + bevacizumab vs. 2.3 with IFL + placebo | [48] |
| Eastern Cooperative Oncology Group Study E3200 | III | FOLFOX47 + bevacizumab vs. FOLFOX4 without bevacizumab vs. bevacizumab alone | After first-line treatment with irinotecan and a fluoropyrimidine | Primary endpoint: OS -mOS: 12.9 months with FOLFOX4 + bevacizumab vs. 10.8 months with FOLFOX4 alone (HR=0.75, p = 0.0011) vs. 10.2 months with bevacizumab alone -mPFS: 7.3 months with FOLFOX4 + bevacizumab vs. 4.7 months with FOLFOX4 alone (HR=0.61; p = 0.0001) vs. 2.7 months with bevacizumab alone -ORR8: 22.7% with FOLFOX4+bevacizumab vs. 8.6% with FOLFOX4 alone vs. 3.3% with bevacizumabalone (p = 0.0001 for FOLFOX4 + bevacizumab vs. FOLFOX4). |
-any G-3 or 4 AE9: 75% with FOLFOX4 + bevacizumab vs. 61% with FOLFOX4 vs. 36% with bevacizumab alone -higher rates of G3 or 4 neuropathy, hypertension, bleeding and vomiting with FOLFOX4 + bevacizumab vs. FOLFOX4 |
[49] |
| ML1814710 | III | Second-line chemotherapy with or without bevacizumab | Second-line treatment after progressing up to 3 months, after discontinuing first-line chemotherapy + bevacizumab | Primary endpoint: OS -mOS: 11.2 months with chemotherapy + bevacizumab vs. 9.8 months with chemotherapy (HR = 0.81, 95% CI11: 0.69–0.94; unstratified log-rank test p = 0.0062) |
-G3-G5 TRAEs12: neutropenia (16% vs. 13%), diarrhea (10% vs. 8%) asthenia (6% vs. 4%), bleeding, or hemorrhage (2% vs. <1%), gastrointestinal perforation (2% vs. <1%) and venous thromboembolisms (5% vs. 3%) in the chemotherapy + bevacizumab arm vs. chemotherapy alone arm, respectively. Treatment-related deaths: 4 in the chemotherapy+bevacizumab group vs. 3 in the chemotherapy alone group | [50] |
| TRIBE13 | III | FOLFOXIRI14 + bevacizumab vs. FOLFIRI15 + bevacizumab | First line | Primary endpoint: PFS16 -mPFS: 12.1 months vs. 9.7 months, HR 0.75, 95% CI: 0.62–0.90; p = 0.003 -mOS: 29.8 months (95% CI: 26·0–34·3) vs. 25·8 months (22.5–29.1) |
-G3-G4 neutropenia, diarrhea, stomatitis, and neurotoxicity significantly higher in the experimental group -No significant differences in bevacizumab-related AE - Similar incidence of SAEs17 (20.4% vs. 19.7%, p = 0.91) |
[51,52] |
| TRIBE-2 | III | FOLFOXIRI + bevacizumab →PD18→ reintroduction of the same regimen vs. mFOLFOX619 + bevacizumab → PD→ FOLFIRI + bevacizumab | First-line treatment | Primary endpoint: PFS220 -mPFS221 = 19.2 months (95% CI: 17.3–21.4) vs. 16.4 months (15.1–17.5) (HR = 0 = 74, 95% CI: 0.63–0.88; p = 0.0005). |
First line treatment: -G3-G4 diarrhea (17% vs. 5%), neutropenia (50% vs. 21%), and arterial hypertension (7% vs. 10%); in –SAEs:25% vs. 17% -treatment-related deaths: 8 vs. 4 After first PD: no substantial differences G3-G4 (except neurotoxicity, only reported in the experimental group (5%) -SAEs 15% vs. 12% -3 treatment-related deaths vs. 4 |
[53] |
| AVEX22 | III | Capecitabine + bevacizumab vs. capecitabine | First line | Primary endpoint: PFS -mPFS: 9.1 months (95% CI: 7.3–11.4) vs. 5.1 months (4.2–6.3); HR 0.53 (0.41–0.69); p < 0·0001) |
-G ≥3: 40% vs. 22% -SAEs: 14% vs. 8% -G ≥3 AE of special interest: HFS23 (16% vs. 7%), diarrhea (7% vs. 7%), and venous thromboembolic events (8% vs. 4%) -Any grade AE of special interest for bevacizumab: hemorrhage (25% vs. 7%) -Treatment-related deaths: 5 vs. 4 |
[55] |
| TASCO-124 | II | Trifluridine/tipiracil + bevacizumab vs. capecitabine + bevacizumab | First line | Primary endpoint: PFS -mPFS: 9.2 months vs. 7.8 months (HR=0.71, 95% CI: 0.48, 1.06) |
-SAEs: 54.5%in the experimental arm vs. 57.9% in the control arm; serious febrile neutropenia 3.9% In both arms | [54] |
| BACCI25 | II | Capecitabine+bevacizumab+ atezolizumab vs. capecitabine+bevacizumab | Progression on 5-FU26, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR27 therapy (if RAS28 wt29) | Primary endpoint: PFS -mPFS: 3.3 months (2.1–6.2) with capecitabine+bevacizumab + atezolizumab vs. 4.4 months (4.1–6.4) with capecitabine + bevacizumab |
G ≥3: hypertension (9% vs. 7%), HFS (6% vs. 4%), and diarrhea (7% vs. 2%). | [57] |
| SOLSTICE30NCT03869892 | III | Trifluridine/tipiracil + bevacizumab vs. capecitabine + bevacizumab | First line.Not candidates for intensive chemotherapy | Primary endpoint: PFS | Ongoing | [56] |
| AtezoTRIBE31NCT03721653 | II | FOLFOXIRI–bevacizumab-atezolizumab vs. FOLFOXIRI–bevacizumab | First line | Primary endpoint: PFS | Ongoing | - |
Note: 1vs. = versus; 2OS = overall survival; 3mOS = median overall survival; 4HR = hazard ratio; 5mPFS = median progression-free survival; 6RR = response rate; 7FOLFOX4 = oxaliplatin, 5-fluorouracil, leucovorin – 4; 8ORR = objective response rate; 9AE = adverse event; 10ML18147 = Continuation of bevacizumab after first progression in metastatic colorectal cancer; 11CI: = confidence interval; 12TRAEs = treatment-related adverse events; 13TRIBE = Triplet plus bevacizumab; 14FOLFOXIRI = oxaliplatin, irinotecan, leucovorin, 5-fluorouracil; 15FOLFIRI = irinotecan, 5-fluorouracil, leucovorin; 16PFS = progression free survival; 17SAEs = serious adverse events; 18PD = progressive disease; 19mFOLFOX6 = modified oxaliplatin, 5-fluorouracil, leucovorin – 6; 20PFS2 = progression free survival 2; 21mPFS2 = median progression-free survival 2; 22AVEX = AVastin in the Elderly with Xeloda; 23HFS = hand foot syndrome; 24TASCO-1 = open-label, randomised, non-comparative phase 2 study evaluating S 95005 (TAS-102) plus bevacizumab and capecitabine plus bevacizumab in patients with previously untreated metastatic COlorectal cancer who are non-eligible for intensive therapy-1 study; 25BACCI = Phase II Randomized, Double-Blind, Placebo-Controlled Study of Capecitabine Bevacizumab Plus Atezolizumab Versus Capecitabine Bevacizumab Plus Placebo in Patients With Refractory Metastatic Colorectal Cancer; 265-FU = 5-fluorouracil; 27anti-EGFR = anti-epidermal growth factor receptor; 28RAS = rat sarcoma; 29wt = wild type; 30SOLSTICE = An open-label, randomised, phase III Study cOmparing trifLuridine/tipiracil (S 95005) in combination with bevacizumab to capecitabine in combination with bevacizumab in firST-line treatment of patients with metastatIC colorectal cancer who are not candidatE for intensive therapy; 31AtezoTRIBE = randomized phase II study of folfoxiri plus Bevacizumab plus atezolizumab versus folfoxiri plus Bevacizumab as first-line treatment of unresectable Metastatic colorectal cancer patients.