Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

Salgia, Ravi; Patel, Premal H.; Bothos, John; Yu, Wei; Eppler, Steve; Hegde, Priti S.; Bai, Shuang; Kaur, Surinder; Nijem, Ihsan; Catenacci, Daniel V.T.; Peterson, Amy; Ratain, Mark J.; Polite, Blasé N.; Mehnert, Janice M.; Moss, Rebecca A.

doi:10.1158/1078-0432.ccr-13-2070

Cited by 62 publications

(45 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although sample size was limited, no relationship was observed between dose and emibetuzumabrelated AEs. Peripheral edema has been suggested as a potential on-target class effect for therapies targeting the MET/HGF pathway (17). Ryan and colleagues (18) noted peripheral edema by treatment with rilotumumab (a fully human mAb against HGF), and Salgia and colleagues reported peripheral edema following treatment with onartuzumab (a monovalent MET Ab) at doses !10 mg/kg (17).…”

Section: Discussionmentioning

confidence: 99%

“…Peripheral edema has been suggested as a potential on-target class effect for therapies targeting the MET/HGF pathway (17). Ryan and colleagues (18) noted peripheral edema by treatment with rilotumumab (a fully human mAb against HGF), and Salgia and colleagues reported peripheral edema following treatment with onartuzumab (a monovalent MET Ab) at doses !10 mg/kg (17). In the current study, non-emibetuzumab-related peripheral edema was reported for monotherapy in 2 patients at the lowest dose level, and 1 patient each at the 700-mg and 1,400-mg dose levels.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Rosen

Goldman

Algazi

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGFdependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab.Experimental Design: The study comprised a 3þ3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ! grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab þ erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab þ erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression.Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Rosen

Goldman

Algazi

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The lack of clinical activity of treatment with c-MET inhibitors for the 7 MET-amplified patients reported here was disappointing. Results from prior trials detected early activity of these agents in patients selected by c-MET protein overexpression and MET amplification in GECs (7,44), MET germline mutations in papillary renal cell cancer (24), and chromosome polyploidy in gastric cancer (45). However, it is to be noted, for patients with NSCLC, both onartuzumab and tivantinib in combination with EGFR did not meet their endpoints in an unselected population.…”

Section: Discussionmentioning

confidence: 99%

Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic

Jardim

Tang

Gagliato

et al. 2014

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P ¼ 0.007), high-grade tumors (P ¼ 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR ¼ 1.12; 95% confidence intervals, 0.83-1.85; P ¼ 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336-45. Ó2014 AACR.

show abstract

“…Also, recurrent amplification of genes associated with the receptor tyrosine kinase pathway, such as EGFR, ERBB2, ERBB3, JAK2, FGFR2, and MET, and the angiogenesis pathway, such as VEGFA, have been reported in GC [4,5]. With the exception of a subset of patients with ERBB2 amplification who experienced benefits from trastuzumab [6], targeted agents for aberrant gene amplification have not yet been successful in therapeutic applications [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer

et al. 2015

View full text Add to dashboard Cite

Background Little is known about cytokine and angiogenic factors (CAFs) in gastric cancer (GC) in terms of tumor classification and prognostic value. Here, we aimed to correlate CAF signature with overall survival (OS) in GC. Methods We measured pretreatment serum levels of 52 kinds of CAFs in 68 GC patients who were treated with fluoropyrimidine and platinum combination chemotherapy using multiplex bead immunoassays and enzyme-linked immunosorbent assay. We evaluated correlations between CAF levels and pathological features and OS. Results Three distinct patient groups were identified: one with high levels of proangiogenic factors, another with high levels of proinflammatory factors, and the other with high levels of both factors. Eleven CAFs [interleukin (IL)-2 receptor-alpha, growth-regulated alpha protein, hepatocyte growth factor, macrophage colony-stimulating factor, stromal cell-derived factor, IL-6, IL-8, IL-10, interferongamma, vascular endothelial growth factor, and osteopontin] were independently correlated with poor OS. Clustering analysis of these 11 CAFs revealed distinct high and low 11-CAF signature groups. High 11-CAF signature was associated with shorter OS (10.1 vs. 17.9 months, p = 0.026) along with poor performance status, and the presence of signet ring cell components in multivariate analysis of OS (HR 1.76, p = 0.029). The patients' traditional clinicopathological characteristics were not significantly different between the high and low 11-CAF signature groups. Conclusion Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies.

show abstract

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

Cited by 62 publications

References 25 publications

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic

Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer

Contact Info

Product

Resources

About