Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab—20 Years of Therapeutic Success and Controversy
Simple Summary
Abstract
1. Introduction
2. Mechanisms of Tumoral Angiogenesis
3. Bevacizumab—One of the Most Relevant Anti-Angiogenetic Drugs in Solid Tumors
4. Efficacy and Safety of Bevacizumab in Solid Tumors
4.1. Colorectal Cancer
Study Name | Study Type | Cohort | Intervention | Outcomes/Endpoints | Main Results |
---|---|---|---|---|---|
Colorectal cancer | |||||
AVF2107g [49,50,51] | Phase III, multicenter, active-controlled study, sponsored by Genentech, first-line therapy | 813 patients in 163 centers, mCRC | Arm I: 411 patients—IFL for a total of 4 weeks of each 6 week-cycle (Saltz regimen) + PL. | Primary endpoint: OS Secondary endpoints: PFS, RR, duration of response, QoL and patient safety. | Adding Bev to IFL improved OS (20.3 months in arm II vs. 15.6 months in arm I, p < 0.0001). Adding Bev to IFL also improved PFS (10.6 vs. 6.2 months, p < 0.0001), RR (34.6% in arm I vs. 44.5% in arm II, p-value = 0.0036), and the duration of response (10.35 vs. 7.06 months). Adding Bev did not lead to a more rapid worsening of QoL compared to standard first-line chemotherapy (2.89 vs. 2.73 months). |
Arm II: 402 patients—IFL for a total of 4 weeks of each 6 week-cycle (Saltz regimen) + Bev 5 mg/kg q2w. | |||||
Arm III *: 110 patients—FL + Bev 5 mg/kg q2w. | |||||
AVF0780g [52,53] | Phase II, randomized, multicenter, multidose study sponsored by Genentech, first-line therapy | 104 patients with mCRC | Arm I: 36 patients—FL for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen). Arm II: 35 patients—FL for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) + Bev 5 mg/kg. Arm III: 33 patients—FL for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) + Bev 10 mg/kg. | PFS, RR, OS, disease progression. | Disease progression was observed in 26/36 patients in arm I, in 22/35 patients in arm II and in 23/33 patients in arm III. The median PFS in the 3 arms was 5.2, 9 (p = 0.005), and 7.2 months, respectively (p = 0.236). A statistically significant improvement in PFS was observed in arm II, but no significant was observed for higher Bev doses. OS: 13.6 (arm I), 17.7 (arm II) and 15.2 months (arm III), respectively. No significant differences in OS were observed between the arms, but only a trend towards improvement in arm II. |
AVF2192g [51] | Phase II, randomized, double-blind, active-controlled | 209 patients with mCRC, patients who were not optimal candidates for 1st line irinotecan treatment | Arm I: 105 patients—FL + PL Arm II: 104 patients—FL + Bev 5 mg/kg q2w. | PFS, RR, OS, duration of response. | Improved PFS in arm II: 9.2 vs. 5.5 months (p = 0.0002). Duration of response: 9.2 vs. 6.8 months favoring Bev arm. Non-significant results: improvement in OS in arm II—16.6 vs. 12.9 months (p = 0.16); better RR in arm II—26% vs. 15.2% (p = 0.055). |
ECOG E3200 [54] | Phase III randomized, active-controlled, open-label trial, second-line therapy | 829 patients with advanced/metastatic CRC, Bev-naive patients | Arm I: 292 patients—FOLFOX-4 Arm II: 293 patients—FOLFOX-4 + Bev Arm III: Bev in monotherapy. | OS, PFS, RR. | Adding Bev to FOLFOX-4 determined significant improvements in OS (13 vs. 10.8 months, p = 0.0012), PFS (7.5 vs. 4.5 months, p < 0.0001) and RR (22.2% vs. 8.6%, p < 0.0001). No significant benefits were observed for Bev monotherapy compared to standard chemotherapy. |
Lung cancer | |||||
ECOG E4599 [55] | Phase III, randomized, first-line treatment | 878 patients with advanced, recurrent and metastatic NSCLC (stage IIIB or IV) | Arm 1 (444 subjects)—standard chemotherapy carboplatin + paclitaxel Arm 2 (434 subjects)—carboplatin + paclitaxel in combination with Bevacizumab. | OS, PFS, RR. | Adding Bev determined increased OS (12.3 vs. 10.3 months, p = 0.003), PFS (6.2 vs. 4.5 months, p < 0.001) and better RR (35% vs. 15%, p < 0.001). There were 15 deaths associated with Bev therapy, including 5 due to massive pulmonary hemorrhage (increased risk of severe adverse effects). OS in patients with adenocarcinoma histology was twice as high compared to the total patient population suggesting an additional benefit of Bev in this subset of patients. |
AVAiL [56] | Phase III, placebo-controlled, first-line therapy | 1043 patients with advanced or recurrent NSCLC | Arm 1 (326 subjects): standard chemotherapy (cisplatin + gemcitabine) and PL. Arm 2 (331 subjects): standard chemotherapy + 7.5 mg/kg Bev. Arm 3 (329 subjects): standard chemotherapy + 15 mg/kg Bevacizumab. Bev or PL were administered until disease progression. | OS, PFS. | The final analysis confirmed the efficacy of adding Bevacizumab to the cisplatin + gemcitabine combination chemotherapy, demonstrating a statistically significant PFS benefit in both the 7.5 and 15 mg/kgc groups (p = 0.0003 and p = 0.0456, respectively). The PFS benefit did not translate into overall survival benefits, with OS being >13 months in all arms. No change in the safety profile was observed in elderly patients (over 65) compared to the entire group. |
AVAPERL [57,58] | Phase III, randomized, maintenance | 253 Patients with advanced non-squamous NSCLC received first-line Bev+ cisplatin + pemetrexed for 4 cycles. Those achieving response or stable disease were randomized 1:1 to maintenance | Arm 1 (125 patients)—Bev 7.5 mg/kg Arm 2 (128 patients) Bev 7.5 mg/kg plus pemetrexed 500 mg/m2 q3w Treatment continued until disease progression or unacceptable toxicity. | PFS, OS. | The combination therapy Bev + permetrex proved superior as maintenance after achieving disease stability with cisplatin/permetrex chemotherapy + Bev (50% reduction in the risk of progression compared with Bev monotherapy (median PFS: 10.2 vs. 6.6 months), but without an OS benefit. |
JO25567 [59,60,61] | Phase III, open-label, randomized, multicenter, combination therapy | 152 Japanese patients with stage IIIB/IV or postoperative recurrent NSCLC, chemotherapy-naïve, with EGFR mutations | Compared erlotinib + Bev (15 mg/kg every 21 days—75 subjects) combination therapy with erlotinib alone (erlotinib 150 mg once daily—77 subjects). | Risk of disease progression. | The study proved the superiority of the combination therapy (46% reduction in the risk of progression; p = 0.015). Based on this study, the erlotinib + Bev combination therapy was approved for the treatment of patients with advanced/metastatic NSCLC harboring EGFR mutations. |
IMpower150 [62,63] | Phase III, international, open-label 1:1:1l, randomized trial conducted at 240 study centers in 26 countries, First-line | stage IV or recurrent metastatic non squamous NSCLC (for which they had not previously received chemotherapy | Compared Atezolizumab and Bev + chemotherapy combination to Bev/Atezolizumab + chemotherapy alone. | PFS, OS. | 38% reduction in the risk of progression (p < 0.001) in the Atezolizumab combination arm. This benefit was observed regardless of EGFR/ALK status These results led to the approval of the combination in the first-line treatment of NSCLC. |
Breast cancer | |||||
ECOG E2100 [64] | Phase III, Randomized 1:1, open-label | 722 patients with locally advanced, recurrent, or metastatic breast cancer who had not previously received Bev | Arm 1: Paclitaxel Arm 2: Paclitaxel + Bev. | OS, PFS, RR. | The addition of Bev to chemotherapy resulted in a 5.5 month increase in median PFS (HR 0.48; 95% CI 0.39–0.61; p < 0.0001), but no statistically significant improvement in OS (HR 0.87; 95% CI 0.72–1.05; p = 0.137). The RR was higher in the Bev arm compared to control (48.9% vs. 22.2%). |
Ovarian, fallopian tube and primary peritoneal cancer | |||||
GOG-0218 [65] | Phase III, double-blind, PL-controlled, randomized 1:1:1, first-line therapy | 1873 women with stage III or IV primary ovarian, fallopian tube, or peritoneal cancer who had undergone suboptimal cytoreductive surgery | Arm I: platinum-based chemotherapy Arm II: platinum-based chemotherapy + Bev 15 mg/kg. Arm III: platinum-based chemotherapy + Bev followed by Bev maintenance. | PFS, OS. | The addition of Bev to chemotherapy resulted in a statistically significant increase in PFS (from 10.3 to 14.1 months, p ≤ 0.001). Although there was no significant difference in OS between the arms, in the subgroup of patients with stage IV disease, combined therapy followed by Bev maintenance led to an improvement in OS (median OS 42.8 vs. 32.6 months). |
ICON7 [66] | Phase III, open-label, randomized 1:1, first-line therapy | 1528 women diagnosed with stage III or IV primary ovarian, fallopian tube, or peritoneal cancer who underwent cytoreductive surgery | Arm I: carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2), q3w, for 6 cycles. Arm II: carboplatin + paclitaxel and Bev 7.5 mg/kg concurrently q3w for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. | PFS, OS. | The final published results did not prove a significant benefit in PFS or OS. Only the analysis of the subgroup of high-risk patients demonstrated an improvement in PFS in the Bevacizumab-treated arm (16.0 vs. 10.5 months; p = 0.001). |
PAOLA-1 [67,68] | Phase III, randomized 2:1, double-blind, PL-controlled | 806 patients with newly diagnosed, advanced, high-grade ovarian cancer which responded to first-line platinum–taxanes chemotherapy plus Bev. Patients were eligible regardless of surgical outcome or BRCA mutation status. | Patients were randomly assigned in a 2:1 ratio to receive Olaparib tablets (300 mg twice daily) or PL for up to 24 months; all the patients received Bev at a dose of 15 mg/kg q3w for up to 15 months in total. | PFS. | Initial results indicate a PFS benefit when Bev + Olaparib (PARP inhibitor) combination therapy is used as maintenance. The median PFS was 22.1 months with Olaparib and 16.6 months with PL (p < 0.001). The addition of maintenance Olaparib provided a significant PFS and OS benefit, substantial in patients with homologous-recombination deficiency tumors, including those without a BRCA mutation. |
Cervical cancer | |||||
GOG-240 [69] | Phase III, multicenter, open label, randomized | 452 patients with recurrent/persistent cervical cancer, not amenable to curative treatment with surgery and/or radiation therapy. | Arm I: paclitaxel + cisplatin/topotecan Arm II: paclitaxel + cisplatin/topotecan and Bev. | Risk of death. Risk of disease progression. | 23% reduction in the risk of death (p = 0.007) in the Bev arm. 33% reduction in the risk of disease progression (p = 0.002) in the Bev arm. Adding Bev determined increased OS (17.0 vs. 13.3 months, p = 0.004) and RR (48% vs. 36%, p = 0.008). Bev was associated with an increased incidence of hypertension, thromboembolic events and gastrointestinal fistulas. |
Brain tumors | |||||
AVF3708g [70] | Phase II, open-label, non-comparative, randomized | 167 patients with relapsed or progressive glioblastomas. | Arm I: Bev monotherapy Arm II: Bev + irinotecan | RR, PFS. | Improvement in PFS compared to historical controls: by 4.2 months when Bev is used as monotherapy and by 5.6 months when Bev was combined with irinotecan. |
AvaGlio [71] | Phase III, first-line | Patients with newly diagnosed glioblastoma in first or second relapse. | Arm I: radiotherapy and temozolomide + PL. Arm II: radiotherapy and temozolomide + Bev. | Reduction in the risk of disease progression through the addition of Bev to radiotherapy + temozolomide, compared to control. |
4.2. Lung Cancer
4.3. Breast Cancer
4.4. Renal Cell Carcinoma
4.5. Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
4.6. Cervical Cancer
4.7. Brain Tumors
5. Controversies Regarding Bevacizumab
5.1. Approval Process and Pivot-Trials Biases
5.2. Resistance to Bevacizumab Therapy
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Chitoran, E.; Rotaru, V.; Stefan, D.-C.; Gullo, G.; Simion, L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab—20 Years of Therapeutic Success and Controversy. Cancers 2025, 17, 1126. https://doi.org/10.3390/cancers17071126
Chitoran E, Rotaru V, Stefan D-C, Gullo G, Simion L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab—20 Years of Therapeutic Success and Controversy. Cancers. 2025; 17(7):1126. https://doi.org/10.3390/cancers17071126
Chicago/Turabian StyleChitoran, Elena, Vlad Rotaru, Daniela-Cristina Stefan, Giuseppe Gullo, and Laurentiu Simion. 2025. "Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab—20 Years of Therapeutic Success and Controversy" Cancers 17, no. 7: 1126. https://doi.org/10.3390/cancers17071126
APA StyleChitoran, E., Rotaru, V., Stefan, D.-C., Gullo, G., & Simion, L. (2025). Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab—20 Years of Therapeutic Success and Controversy. Cancers, 17(7), 1126. https://doi.org/10.3390/cancers17071126