Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer

Abstract

Purpose Phase III studies of bevacizumab in advanced pancreas cancer (APCA) demonstrated no improvement in outcome. No validated biomarkers for bevacizumab efficacy exist. We evaluated bevacizumab-related hypertension (B-HTN) as a biomarker in APCA patients in a pooled analysis from 4 prospective clinical trials of gemcitabine-based therapy combined with bevacizumab. Materials and Methods Data were collected from individual databases from 4 prospective, single-arm phase II trials. Patients were grouped according to B-HTN or no hypertension (HTN), and patients with HTN were further grouped according to highest Common Terminology Criteria for Adverse Events grade of HTN: grade 1-2 or grade 3-4. Clinical outcomes of overall survival, time to progression, overall response rate (ORR), and disease control rate (ORR + SD > 16 wk) were compared. Results A total of 163 patients with stage IV APCA and Eastern Cooperative Oncology Group 0-1 were included. Median age was 59 years (range, 33 to 85 y). Thirty-four patients had B-HTN, and 129 patients had no HTN. Prognostic factors were balanced between groups. Patients with any grade B-HTN had a significantly improved median overall survival (13.1 vs. 8.1 mo, P = 0.0006), median time to tumor progression (7.6 vs. 5.5 mo, P = 0.0074), ORR (47% vs. 16%, P = 0.0001), and disease control rate (85% vs. 59%, P = 0.004). There were no differences in outcomes according to HTN grade (1-2 [N = 16] vs. 3-4 [N = 18]). Conclusions APCA patients who develop any grade of B-HTN appear to derive benefit from bevacizumab. Additional investigation is needed to identify subgroups of patients who develop B-HTN and are more likely to benefit from bevacizumab.

Treatment‐emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT)

“…For example, an association between TE‐HTN and improved OS has been reported with bevacizumab when it has been added to chemotherapy for patients with non–small cell lung carcinoma . Similar correlations have been shown with other VEGFR inhibitors in a variety of tumor types, including renal cell carcinoma, colorectal carcinoma, and pancreatic cancer . As a result, HTN has been proposed as a biomarker of clinical outcomes for these agents.…”

“…2 Similar correlations have been shown with other VEGFR inhibitors in a variety of tumor types, including renal cell carcinoma, colorectal carcinoma, and pancreatic cancer. [3][4][5] As a result, HTN has been proposed as a biomarker of clinical outcomes for these agents. The higher incidence of severe HTN with lenvatinib treatment compared with other agents may be due to its more potent inhibition of VEGFR2.…”

“…Hypertension (HTN) is an established on‐target class effect of vascular endothelial growth factor receptor (VEGFR) inhibitors . HTN is not only a common side effect of VEGFR inhibition but also has been shown to correlate with tumor response and survival in a variety of cancer settings, including non–small cell lung carcinoma, renal cell carcinoma, colorectal carcinoma, and pancreatic carcinoma …”

“…1 HTN is not only a common side effect of VEGFR inhibition but also has been shown to correlate with tumor response and survival in a variety of cancer settings, including non-small cell lung carcinoma, renal cell carcinoma, colorectal carcinoma, and pancreatic carcinoma. [2][3][4][5] Lenvatinib is an oral, multikinase inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, ret proto-oncogene (RET), stem cell factor receptor (KIT), and platelet-derived growth factor receptor a (PDGFRa). 6,7 Lenvatinib has been approved in the United States, Europe, and Japan for the treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (RR-DTC) on the basis of results from the pivotal phase 3 trial Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).…”

Molecular Markers Predictive of Chemotherapy Response in Colorectal Cancer

“…Notably, bevacizumab-related hypertension occurs more often in individuals who respond to treatment [43, 44]. Consequently, hypertension is considered a pharmacodynamic biomarker, but lacks the predictive capability needed to guide the selection of optimized individual therapeutic regimens.…”