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

Garcia-Carbonero, Rocio; Cutsem, Eric Van; Rivera, Fernando; Jassem, Jacek; Gore, Ira; Tebbutt, Niall C.; Braiteh, Fadi; Argiles, Guillem; Wainberg, Zev A.; Funke, Roel; Anderson, Maria; McCall, Bruce; Stroh, Mark; Wakshull, Eric; Hegde, Priti S.; Ye, Weilan; Chen, Daniel S.; Chang, Ilsung; Rhee, Ina; Hurwitz, Herbert

doi:10.1634/theoncologist.2016-0133

Cited by 23 publications

(17 citation statements)

References 19 publications

(33 reference statements)

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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 = .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) .…”

Section: Discussionsupporting

confidence: 70%

“…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%

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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

Pawel¹,

Spigel²,

Ervin

et al. 2018

The Oncologist

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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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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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

Pawel¹,

Spigel²,

Ervin

et al. 2018

The Oncologist

Self Cite

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“…The overall treatment outcomes in both arms also matched the historical performance of front‐line bevacizumab/mFOLFOX‐6 , thereby making it highly implausible that the therapeutic potency of vanucizumab was confounded by the study conduct adversely interfering with delivery or efficacy of the regimens. Similarly, other emerging antiangiogenic approaches to potentiate the anti–VEGF‐A effect of bevacizumab in the first‐line setting of mCRC by targeting the mesenchymal‐epithelial transition receptor with onartuzumab or the vascular‐restricted, extracellular matrix protein epidermal growth factor‐like domain 7 with parsatuzumab were also unsuccessful.…”

Section: Discussionmentioning

confidence: 99%

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

Bendell

Sauri

Gracian³

et al. 2019

The Oncologist

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Background Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC. Patients and Methods All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS. Results One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. Conclusion Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC. Implications for Practice This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.

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“…Possibly due, at least in part, to this immune escape, higher levels of circulating and tumoral EGFL7 correlate with a worse outcome in various cancers [8,9]. Unfortunately, phase II clinical trials in small cell lung cancer [10] and colorectal cancer [11] both failed to show a benefit of the anti-EGFL7-antibody parsatuzumab in combination with the anti-VEGF antibody bevacizumab and chemotherapy. In ischemic and inflammatory conditions, EGFL7 similarly limits the upregulation of the adhesion molecule ICAM-1 on peripheral endothelium and increases survival of endothelial cells [12].…”

Section: The Putative Role Of Egfl7 In Cancer Stroke and Systemic Scmentioning

confidence: 99%

EGFL7 – a potential therapeutic target for multiple sclerosis?

Uphaus

Zipp

Larochelle

2018

Expert Opinion on Therapeutic Targets

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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 23 publications

References 19 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

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

EGFL7 – a potential therapeutic target for multiple sclerosis?

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