Early hypertension is associated with better clinical outcomes in gastric cancer patients treated with ramucirumab plus paclitaxel

Anti-vascular endothelial growth factor (VEGF) therapeutics such as bevacizumab, which are widely used in cancer treatment, commonly leads to hypertension. Moreover, bevacizumab-induced hypertension is associated with improved clinical outcomes in several cancers. We retrospectively analyzed 89 patients with histologically confirmed advanced gastric cancer who received the human monoclonal anti-VEGF receptor-2 antibody ramucirumab plus paclitaxel at our hospital between June 2015 and October 2016 to evaluate the impact of treatment-associated hypertension occurring within the first two treatment cycles (“early hypertension”) on outcome. The objective response rate was 40%, median progression-free survival was 5.4 months, and overall survival was 10.4 months, which is similar to previous reports. Early hypertension in patients who received more than two cycles of ramucirumab + paclitaxel was associated with longer progression-free and overall survival. Objective response rates were also higher in patients with early hypertension. These data indicate that early hypertension may be predictive of better outcomes in gastric cancer patients who receive ramucirumab + paclitaxel treatment.

[1]  J. Tabernero,et al.  D04Exposure-response (E-R) relationship of Ramucirumab (RAM) from a global, randomized, double-blind, Phase 3 study of patients (Pts) with advanced 2nd line colorectal cancer , 2016 .

[2]  David C. Smith,et al.  Phase II Study Evaluating the Effect of Concomitant Ramucirumab on the Pharmacokinetics of Docetaxel in Patients with Advanced Solid Tumors , 2016 .

[3]  J. Ajani,et al.  Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab , 2016, British Journal of Cancer.

[4]  David C. Smith,et al.  Lack of pharmacokinetic drug–drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors , 2016, Cancer Chemotherapy and Pharmacology.

[5]  J. Mackey,et al.  Reply to H.J. Lee et al. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  J. Mackey,et al.  Genetics of ramucirumab-associated hypertension in the ROSE/TRIO-012 breast cancer trial. , 2015 .

[7]  F. Cappuzzo,et al.  Exposure-response relationship for ramucirumab (RAM) from the randomized, double-blind, phase III REVEL trial (docetaxel [DOC] vs DOC plus RAM) in second-line treatment of metastatic non-small cell lung cancer (NSCLC). , 2015 .

[8]  J. Ajani,et al.  Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer. , 2015 .

[9]  M. Buyse,et al.  a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer , 2014 .

[10]  K Nishikawa,et al.  Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Naotoshi Sugimoto,et al.  Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. , 2014, The Lancet. Oncology.

[12]  T. Choueiri,et al.  A phase 2, single‐arm study of ramucirumab in patients with metastatic renal cell carcinoma with disease progression on or intolerance to tyrosine kinase inhibitor therapy , 2014, Cancer.

[13]  C. Fuchs,et al.  Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial , 2014, The Lancet.

[14]  N. Sugimoto,et al.  Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.

[16]  E. Baba,et al.  Erratum to: Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study , 2012, Gastric Cancer.

[17]  E. Baba,et al.  Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study , 2012, Gastric Cancer.

[18]  Inkyung Jung,et al.  A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. , 2012, European journal of cancer.

[19]  J. Schiller,et al.  Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  D. Camidge,et al.  Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  H. Hurwitz,et al.  Vascular Endothelial Growth Factor Receptor 2 Controls Blood Pressure by Regulating Nitric Oxide Synthase Expression , 2009, Hypertension.

[22]  R. Berardi,et al.  Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  B. Lévy,et al.  Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Masahiro Takeuchi,et al.  S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. , 2008, The Lancet. Oncology.

[25]  H. Izzedine,et al.  Hypertension as a predictive factor of Sunitinib activity. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  Marc Peeters,et al.  Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  W. Dahut,et al.  Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[28]  Z. Hua.  Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer , 2006 .

[29]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.