Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab

Arnold, D.; Fuchs, Charlie; Tabernero, Josep; Ohtsu, A.; Zhu, A. X.; Garon, Edward B.; Paz-Ares, L.; Baron, Ari David; Okusaka, T.; Yoshino, T.; Yoon, Harry H.; Das, Mayukh; Ferry, David; Zhang, Y.; Lin, Yong; Binder, Polina; Sashegyi, Andreas; Chau, Ian

doi:10.1093/annonc/mdx388.049

Cited by 21 publications

(30 citation statements)

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“…Several low‐grade hypothyroidism events were observed, and approximately 40% of patients experienced grade 3 treatment‐related TEAEs. Overall, the pattern and incidence of TEAEs observed are consistent with the expected individual safety profiles for ramucirumab [13–15] and merestinib [12].…”

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confidence: 73%

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

et al. 2020

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Lessons Learned The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. Background This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. Methods Open‐label phase Ia/b study comprising 3+3 dose‐limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28‐day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. Results Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment‐emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment‐related TEAEs. The most common grade ≥3 treatment‐related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 μg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression‐free survival was 3.3 months (95% confidence interval [CI]: 1.6–4.4). Median overall survival was 8.9 months (95% CI: 3.5–12.7). There were no associations between genetic alterations and efficacy. Conclusion Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker‐unselected, heavily pretreated patients with mCRC.

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confidence: 73%

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

et al. 2020

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“…In the present study, there was no difference in the likelihood of proteinuria depending on anti-angiogenic agents. A previous study suggested that severe renal side effects may be less common with ramucirumab than with bevacizumab 21 . On the other hand, Peng et al showed that the risk of developing all-grade and high-grade proteinuria was substantially higher with aflibercept than with bevacizumab 7 .…”

Section: Discussionmentioning

confidence: 96%

Predictive factors for the development of proteinuria in cancer patients treated with bevacizumab, ramucirumab, and aflibercept: a single-institution retrospective analysis

Kanbayashi

Ishikawa

Tabuchi

et al. 2020

Sci Rep

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The development of proteinuria restricts the dose of anti-angiogenic agents, thereby reducing their efficacy. Thus, this retrospective study was undertaken to identify predictive factors of the development of angiogenesis inhibitor-induced proteinuria, and to elucidate if there is a difference in the likelihood of proteinuria among anti-angiogenic agents or cancer types, to help guide future strategies to improve the safety, efficacy, and quality of life of patients receiving chemotherapy. Between April 2014 and February 2019, 124 cancer patients at our outpatient chemotherapy center who were receiving chemotherapy with bevacizumab, ramucirumab, or aflibercept were enrolled. Variables related to the development of proteinuria were extracted from the patients' clinical records and used for regression analysis. The level of the proteinuria was evaluated based on CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of proteinuria. The Wilcoxon/Kruskal-Wallis test was used to identify significant differences between groups. Significant factors identified included systolic blood pressure (SBP) [odds ratio (OR) = 1.031, 95% confidence interval (CI) = 1.005-1.058; P = 0.0197], number of cycles (OR = 1.049, 95% CI = 1.018-1.082; P = 0.0019), and calcium channel blocker use (OR = 2.589, 95% CI = 1.090-6.146; P = 0.0311). There was no difference among the three anti-angiogenic agents (P = 0.4969) or among cancer types (P = 0.2726) in the likelihood of proteinuria. In conclusion, SBP, number of cycles, and calcium channel blocker use were identified as significant predictors of the development of angiogenesis inhibitorinduced proteinuria. There was no difference among the three anti-angiogenic agents or among cancer types. Anti-angiogenic agents targeting the human vascular endothelial growth factor pathway, such as bevacizumab, ramucirumab, and aflibercept, significantly improve overall survival and progression-free survival in colorectal, lung, gastric, breast cancers and so on 1-5. The toxicity profile of anti-angiogenic agents differs from those of conventional cytotoxic anticancer agents; use of anti-angiogenic agents is commonly associated with elevated

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“…Several phase III studies have shown that the addition of ramucirumab to a chemotherapy regimen improves the overall survival of patients with gastric cancer, gastroesophageal junction adenocarcinoma, and colorectal cancers . Severe adverse events related to vascular endothelial growth factor pathways such as bowel perforation and bleeding have been reported . The safety of the combination of ramucirumab and palliative RT remains unclear because these phase III studies excluded patients receiving RT.…”

Section: Discussionmentioning

confidence: 99%

Severe esophageal stenosis in a patient with metastatic colon cancer following palliative radiotherapy, ramucirumab, and chemotherapy

Akahane

Shirai

Wakatsuki

et al. 2020

Clinical Case Reports

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Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab

Cited by 21 publications

References 0 publications

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

Predictive factors for the development of proteinuria in cancer patients treated with bevacizumab, ramucirumab, and aflibercept: a single-institution retrospective analysis

Severe esophageal stenosis in a patient with metastatic colon cancer following palliative radiotherapy, ramucirumab, and chemotherapy

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