•Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.•Approved in a range of solid tumor indications, bevacizumab is an important part of the ...standard of care in oncology.•The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.•First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab’s initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies.
In the past 15 years, our understanding of VEGF’s role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive.
Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).
We evaluated the association between tumor location and survival parameters in patients ...with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.
Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio HR = .44, 95% confidence interval CI = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.
These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
Ramucirumab (IMC-1121B) is a fully humanized IgG1 monoclonal antibody, targeting the extracellular domain of VEGF receptor 2 (VEGFR2). Numerous Phase I - II trials in various malignancies have shown ...promising clinical antitumor efficacy and tolerability. Most recently, the large Phase III REGARD trial evaluated ramucirumab in patients with refractory metastatic gastric cancer. Patients receiving ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months on placebo.
The purpose of this article is to review the preclinical motivation for VEGFR2-targeted therapies and survey recent data from clinical trials involving ramucirumab, as well as highlight ongoing studies.
Rational multi-target approaches to angiogenesis are needed to overcome resistance mechanisms. Predictive angiogenic biomarkers are also needed to optimize patient selection for novel anti-angiogenic agents.
The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor ...receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors.
Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks.
Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily.
Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.
Anti-VEGF therapies in the clinic Meadows, Kellen L; Hurwitz, Herbert I
Cold Spring Harbor perspectives in medicine,
10/2012, Letnik:
2, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor ...types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies.
Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated ...survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV.
The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival.
The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019).
The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.
Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti-vascular endothelial growth factor therapy to these events remains controversial.
...Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined.
There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment.
The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.
Background
First‐line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5‐fluorouracil/leucovorin/oxaliplatin (FOLFOX) or ...5‐fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI‐BEV) or sequentially (sFOLFOXIRI‐BEV, FOLFOX‐BEV alternating with FOLFIRI‐BEV), versus FOLFOX‐BEV for mCRC.
Patients and Methods
Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, or FOLFOX‐BEV and treated with 4–6‐month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first‐line cFOLFOXIRI‐BEV vs. FOLFOX‐BEV) and progression‐free survival (PFS; pooled first‐line cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV vs. FOLFOX‐BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety.
Results
ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, and FOLFOX‐BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI‐BEV and FOLFOX‐BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI‐BEV versus FOLFOX‐BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5–0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI‐BEV), 9.8% (sFOLFOXIRI‐BEV), and 8.4% (FOLFOX‐BEV). Grade ≥ 3 treatment‐emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI‐BEV), 86.7% (sFOLFOXIRI‐BEV), and 85.6% (FOLFOX‐BEV) of patients, with no increase in serious chemotherapy‐associated TEAEs.
Conclusion
cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX‐BEV, supporting triplet chemotherapy plus BEV as a first‐line treatment option for mCRC.
Implications for Practice
The combination of first‐line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI‐BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI‐BEV or FOLFOX‐BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI‐BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI‐BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI‐BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first‐line treatment options for this population.
摘要
背景。转移性结直肠癌 (mCRC) 的一线治疗通常需要生物制剂，如贝伐单抗 (BEV)，以及 5‐氟尿嘧啶/亚叶酸钙/奥沙利铂 (FOLFOX) 或 5‐氟尿嘧啶/亚叶酸钙/伊立替康 (FOLFIRI)。STEAM (NCT01765582) 评估了BEV 和 FOLFOX/FOLFIRI (FOLFOXIRI) 在同步用药 (cFOLFOXIRI‐BEV) 或序贯用药(sFOLFOXIRI‐BEV，FOLFOX‐BEV 与 FOLFIRI‐BEV 交替使用)的情况下对比 FOLFOX‐BEV 治疗 mCRC 的有效性。
患者和方法。既往未经治疗的 mCRC 患者 (n = 280) 按照 1:1:1 的比例被随机分配使用 cFOLFOXIRI‐BEV、sFOLFOXIRI‐BEV 或 FOLFOX‐BEV，并在进行 4~6 个月的诱导治疗之后接受维持治疗。共同的主要终点为总缓解率(ORR；一线 cFOLFOXIRI‐BEV vs. FOLFOX‐BEV)以及无进展生存期(PFS；联合一线 cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV vs. FOLFOX‐BEV)。次要/探索性终点包括总生存期 (OS)、肝脏切除率、生物标志物分析和安全性。
结果。cFOLFOXIRI‐BEV、sFOLFOXIRI‐BEV 和 FOLFOX‐BEV 的 ORR 分别为 72.0%、72.8% 和 62.1%，中位 PFS 分别为 11.9 个月、11.4 个月和 9.5 个月。组间的 OS 很相似。cFOLFOXIRI‐BEV 和 FOLFOX‐BEV 之间的 ORR 没有显著差异 (p = 0.132)；因此，未达到主要 ORR 终点。无论 RAS 状态如何，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 均在数字方面改进了 ORR 和 PFS。联合同步和序贯 FOLFOXIRI‐BEV 对比 FOLFOX‐BEV 的中位 PFS 更高(11.7 个月vs. 9.5 个月；风险比，0.7；90% 置信区间，0.5–0.9；p < 0.01)。肝脏切除率为 17.2% (cFOLFOXIRI‐BEV)、9.8% (sFOLFOXIRI‐BEV) 和 8.4% (FOLFOX‐BEV)。在 91.2% (cFOLFOXIRI‐BEV)、86.7% (sFOLFOXIRI‐BEV) 和 85.6% (FOLFOX‐BEV) 的患者中观察到治疗相关的 ≥ 3 级不良反应 (TEAE)，与严重化疗相关的 TEAE 没有增加。
结论。 与 FOLFOX‐BEV 对比而言，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 具有良好的耐受性，在数字方面改进了 ORR、PFS 和肝脏切除率，因而支持将三联化疗加 BEV 作为 mCRC 的一线治疗方案。
实践意义:相对于 FOLFIRI‐BEV 或 FOLFOX‐BEV，一线 FOLFIRI 与 FOLFOX 和贝伐单抗(同步 FOLFOXIRI‐BEV)的组合可以为转移性结直肠癌 (mCRC) 患者改进临床结果，但是，该组合方案被认为与毒性增加有关。FOLFOX 和 FOLFIRI(序贯 FOLFOXIRI‐BEV)交替治疗可以提高耐受性。在 II 期 STEAM 试验(即美国患者中最大型的 FOLFOXIRI‐BEV 研究)中，我们发现同步和序贯 FOLFOXIRI‐BEV 对既往未经治疗的 mCRC 患者具有活性和良好的耐受性，因而支持使用此类疗法作为针对此类人群的潜在一线治疗方案。
First‐line treatment for metastatic colorectal cancer is usually a combination of a biologic, such as bevacizumab, with FOLFIRI or FOLFOX; however, these treatments are associated with increased toxicity. This article reports the results of the phase II STEAM trial, which was the largest study of FOLFOXIRI‐BEV in patients in the U.S., comparing the clinical efficacy and tolerability of FOLFOXIRI‐BEV vs FOLFOX‐BEV.
Purpose.
This analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with ...metastatic colorectal cancer (mCRC).
Patients and Methods.
Patient data were pooled from the first‐line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second‐line E3200 RCT. All analyses were based on the intent‐to‐treat population. To assess differences in time‐to‐event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random‐effects (overall) and fixed‐effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).
Results.
The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71–0.90) and progression‐free survival (PFS; HR, 0.57; 95% CI, 0.46–0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin‐based, irinotecan‐based), extent of disease (liver metastases only, extensive disease), age (<65, ≥65 years), Eastern Cooperative Oncology Group performance status (0, ≥1), and KRAS status (wild‐type, mutant) were consistent with the overall analysis. Incidence rates of grade ≥3 hypertension, proteinuria, bleeding, wound‐healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment.
Conclusion.
The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials.
摘要
目的 本分析将来自随机对照试验（RCT）的贝伐珠单抗联合化疗治疗的转移性结直肠癌（mCRC）患者数据汇总至更彻底的临床结果检验中。。
患者和方法 汇总的患者数据来自一线AVF2107、NO16966、ARTIST、AVF0780、AVF2192和AGITG MAX RCT，以及二线E3200 RCT。所有分析基于意向治疗人群。按照治疗（化疗±安慰剂 vs.化疗+贝伐珠单抗）评估时间至事件变量的差异，采用分层随机效应（全体）和固定效应（亚组比较）模型估计汇总风险比（HR）和95%可信区间（CI）。
结果 分析人群包含3763例患者（化疗±安慰剂组1773例，化疗+贝伐珠单抗组1990例）。化疗+贝伐珠单抗治疗与总生存（OS；HR，0.80；95% CI，0.71 ∼ 0.90）和无进展生存（PFS；HR，0.57；95% CI，0.46 ∼ 0.71）的显著改善相关。根据基础化疗（以奥沙利铂为基础和以伊立替康为基础）定义的亚组间OS和PFS、疾病范围（仅肝转移、广泛性疾病）、年龄（<65、≥65岁）、东部肿瘤协作组体能状态（0，≥1），和KRAS状态（野生型、突变）的效应和总分析相一致。贝伐珠单抗治疗≥3级高血压、蛋白尿、出血、伤口愈合并发症、胃肠道穿孔和血栓栓塞事件的发生率升高。
结论 化疗联合贝伐珠单抗可使mCRC患者的OS和PFS显著延长。在检测的临床相关亚组中观察到广泛的PFS获益。本研究观察到的贝伐珠单抗安全性特征和单个临床研究中报告的相一致。The Oncologist 2013;18:1004‐1012
This analysis examined clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). The use of bevacizumab with chemotherapy resulted in statistically significant increases in overall and progression‐free survival for patients with mCRC, and the observed safety profile of bevacizumab was consistent with that reported in individual trials.
Colorectal cancer (CRC) occurs predominantly in older persons. To provide more statistical power to assess risk/benefit in older patients, we examined the clinical benefit of bevacizumab (BV) plus ...fluorouracil-based chemotherapy in first-line metastatic CRC (mCRC) treatment in patients aged > or = 65 years, using data pooled from two placebo-controlled studies.
Pooled efficacy data for 439 patients > or = 65 years old randomized to BV plus chemotherapy (n = 218) or placebo plus chemotherapy (n = 221) in study 1 and study 2 were retrospectively analyzed on an intent-to-treat basis for overall survival (OS), progression-free survival (PFS), and objective response. Safety analysis was based on reports of targeted adverse events in treated patients.
Median OS with BV plus chemotherapy was 19.3 v 14.3 months with placebo plus chemotherapy (hazard ratio HR = 0.70; 95% CI, 0.55 to 0.90; P = .006). Patients treated with BV plus chemotherapy had a median PFS of 9.2 v 6.2 months for placebo plus chemotherapy patients (HR = 0.52; 95% CI, 0.40 to 0.67; P < .0001). The objective response rate was 34.4% with BV plus chemotherapy versus 29.0% with placebo plus chemotherapy (difference not statistically significant). Rates of BV-associated adverse events in the pooled BV plus chemotherapy group were consistent with those reported in the overall populations for the two studies.
Analysis of pooled patient cohorts age >/= 65 years from two similar trials in mCRC indicates that adding bevacizumab to fluorouracil-based chemotherapy improved OS and PFS, similar to the benefits in younger patients. Also, the risks of treatment do not seem to exceed those in younger patients with mCRC.
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