Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer

García‐Carbonero, Rocío; Cutsem, Éric Van; Rivera, Fernando; Jassem, Jacek; Gore, Ira; Tebbutt, Niall C.; Braiteh, Fadi; Argilés, Guillem; Wainberg, Zev A.; Funke, Roel; Anderson, María Inez Padula; McCall, Bruce; Stroh, Mark; Wakshull, Eric; Hegde, Priti S.; Ye, Weilan; Chen, Daniel; Chang, Ilsung; Rhee, Ina; Hurwitz, Herbert I.

doi:10.1634/theoncologist.2016-0133erratum

Cited by 9 publications

(14 citation statements)

References 18 publications

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“…Likewise, secondary outcome measures showed no evidence of benefit: the ORR was 29% in the parsatuzumab arm and 56% in the placebo arm, and the immature HR for OS was 1.1 (95% CI, 0.5-2.2; p 5 .847). These results reinforce the overall lack of efficacy observed with parsatuzumab in a phase II trial in combination with chemotherapy consisting of folinic acid, 5-FU, and oxaliplatin, known as modified FOLFOX6 or mFOLFOX6, plus bevacizumab in CRC (HR for PFS and OS, 1.17 and 0.97, respectively) [4].…”

supporting

confidence: 71%

“…Parsatuzumab (MEGF0444A) is a humanized anti‐EGFL7 IgG1 monoclonal antibody that selectively blocks the interaction between EGFL7 and endothelial cells. Based on the safety profile and evidence of pharmacodynamic modulation observed in a phase Ib trial of parsatuzumab in combination with bevacizumab with or without paclitaxel , parsatuzumab was advanced to two phase II trials, one in colorectal cancer (CRC) and another the current study in NS‐NSCLC, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, fatal hemorrhage is an established safety signal for bevacizumab in this population, and there was no apparent exacerbation of any other bevacizumab-related AEs in patients receiving parsatuzumab. Thus, given that the CRC trial [4] did not demonstrate an increased risk of bleeding associated with parsatuzumab, it appears unlikely that the numerical imbalance observed in this trial is reflective of a significant difference in toxicity.…”

mentioning

confidence: 83%

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Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer

et al. 2018

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Lessons Learned. The lack of efficacy associated with anti‐EGFL7 combined with standard bevacizumab and chemotherapy in this phase II trial in non‐small cell lung carcinoma is consistent with the lack of benefit observed in colorectal carcinoma, highlighting the challenge of enhancing the efficacy of VEGF inhibition in unselected populations.Future efforts with agents like anti‐EGFL7 should be guided by advances in pharmacodynamic and predictive biomarker development for antiangiogenic agents.Background.Epidermal growth factor‐like domain 7 (EGFL7) is an extracellular matrix‐associated protein that is upregulated during angiogenesis and supports endothelial cell survival. This phase II trial evaluated the efficacy of the anti‐EGFL7 antibody, parsatuzumab, in combination with bevacizumab plus platinum‐based therapy for advanced or recurrent nonsquamous non‐small cell lung cancer (NS‐NSCLC).Methods.Patients (n = 104) were randomized to either placebo or parsatuzumab (600 mg) in combination with bevacizumab (15 mg/kg) and carboplatin/paclitaxel, administered on day 1 of each 21‐day cycle. Carboplatin and paclitaxel were administered for up to six cycles. Bevacizumab and parsatuzumab/placebo were administered for a maximum of 24 months.Results.The progression‐free survival (PFS) hazard ratio (HR) was 1.7 (95% confidence interval [CI], 1.0–2.8; p = .047). The median PFS was 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm. The hazard ratio for overall survival (OS) was 1.1 (95% CI, 0.5–2.2; p = .847). The objective response rate (ORR) was 29% in the parsatuzumab arm and 56% in the placebo arm. Overall safety and tolerability were consistent with the established toxicity profile of bevacizumab.Conclusion.There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first‐line NS‐NSCLC.

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supporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

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Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer

et al. 2018

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“…However, it is important to note that miR‐126 appears to constitute an oncogene or tumor suppressor, depending on the type of tumors. While preclinical studies evaluating the therapeutic efficacy of EGFL7‐targeted cancer treatment appear to be promising (Johnson et al, ), a clinical trial where anti‐EGFL7 was combined with conventional chemotherapeutic agents yielded no significant clinical benefits (Garcia‐Carbonero et al, ). It is possible that the clinical response of EGFL7‐targeted therapy is tumor‐specific and that maximum benefits will be observed in a certain group of patients, whilst conferring no favorable therapeutic outcome for others.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, another study by Hansen, Nielsen, Jakobsen, & Sørensen () revealed that the intratumoral expression of EGFL7 is significantly higher in primary tumors from patients with recurrent disease compared with patients without relapse in stage II or III colorectal cancer. Although these studies point to EGFL7 as a promising target for treatment of metastatic colorectal cancer, a randomized phase II clinical trial has found that parsatuzumab (a humanized anti‐EGFL7 antibody) has failed to improve the conventional chemotherapy efficacy in these patients (Garcia‐Carbonero et al, ). This surprising finding highlights the difficulty and challenges of developing an EGFL7‐targeted therapy.…”

Section: The Role Of Egfl7 In Cancer Developmentmentioning

confidence: 99%

EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis

Hong

Kuek

Shi

et al. 2018

Journal Cellular Physiology

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Epidermal growth factor-like domain-containing protein 7 (EGFL7), a member of the epidermal growth factor (EGF)-like protein family, is a potent angiogenic factor expressed in many different cell types. EGFL7 plays a vital role in controlling vascular angiogenesis during embryogenesis, organogenesis, and maintaining skeletal homeostasis. It regulates cellular functions by mediating the main signaling pathways (Notch, integrin) and EGF receptor cascades. Accumulating evidence suggests that Egfl7 plays a crucial role in cancer biology by modulating tumor angiogenesis, metastasis, and invasion. Dysregulation of Egfl7 has been frequently found in several types of cancers, such as malignant glioma, colorectal carcinoma, oral and oesophageal cancers, gastric cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, osteosarcoma, and acute myeloid leukemia. In addition, altered expression of miR-126, a microRNA associated with Egfl7, was found to play an important role in oncogenesis. More recently, our study has shown that EGFL7 is expressed in both the osteoclast and osteoblast lineages and promotes endothelial cell activities via extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and integrin signaling cascades, indicative of its angiogenic regulation in the bone microenvironment. Thus, understanding the role of EGFL7 may provide novel insights into the development of improved diagnostics and therapeutic treatment for cancers and skeletal pathological disorders, such as ischemic osteonecrosis and bone fracture healing.

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Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells

d’Audigier

Susen

Blandinières

et al. 2017

Stem Cell Rev and Rep

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Egfl7 (VE-statin) is a secreted protein mostly specific to the endothelial lineage during development and in the adult and which expression is enhanced during angiogenesis. Egfl7 involvement in human postnatal vasculogenesis remains unresolved yet. Our aim was to assess Egfl7 expression in several angiogenic cell types originating from human bone marrow, peripheral blood, or cord blood. We found that only endothelial colony forming cells (ECFC), which are currently considered as the genuine endothelial precursor cells, expressed large amounts of Egfl7. In order to assess its potential roles in ECFC, Egfl7 was repressed in ECFC by RNA interference and ECFC angiogenic capacities were tested in vitro and in vivo. Cell proliferation, differentiation, and migration were significantly improved when Egfl7 was repressed in ECFC in vitro, whereas miR-126-3p levels remained unchanged. In vivo, repression of Egfl7 in ECFC significantly improved post-ischemic revascularization in a model of mouse hind-limb ischemia. In conclusion, ECFC are the sole postnatal angiogenic cells which express large amounts of Egfl7 and whose angiogenic properties are repressed by this factor. Thus, Egfl7 inhibition may be considered as a therapeutic option to improve ECFC-mediated postnatal vasculogenesis and to optimize in vitro ECFC expansion in order to develop an optimized cell therapy approach.

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Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer

Cited by 9 publications

References 18 publications

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer

EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis

Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells

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