Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program

<div><p>Background</p><p>Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.</p><p>Methods</p><p>Adverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) “gastrointestinal (GI) perforation”, “embolic and thrombotic events, venous (VTE)”, and “embolic and thrombotic events, arterial (ATE)”, and the Adverse Event Group Term (AEGT) “edema.” The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis.</p><p>Results</p><p>A total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1–2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4−65.7% for all grades and from 1.2−14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0−5.6% (grade ≥3, 0−5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0−6.2%) and grade ≥3 (0−6.2%).</p><p>Conclusions</p><p>The frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.</p></div

Frequency of edema in phase II and III studies evaluating onartuzumab.

<p>Bev = bevacizumab, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed.</p><p>*Study OAM4861g had 3 arms: Ona + Bev + Pac (n = 62); Ona + Pbo + Pac (n = 58); Pbo + Bev + Pac (n = 62), referred to here as the control arm.</p><p>Frequency of edema in phase II and III studies evaluating onartuzumab.</p

Frequency of venous thromboembolism (VTE) in phase II and III studies evaluating onartuzumab.

<p>Bev = bevacizumab, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed.</p><p>*Study OAM4861g had 3 arms: Ona + Bev + Pac (n = 62); Ona + Pbo + Pac (n = 58); Pbo + Bev + Pac (n = 62), referred to here as the control arm.</p><p>Frequency of venous thromboembolism (VTE) in phase II and III studies evaluating onartuzumab.</p

Summary of phase II/III double-blind, placebo-controlled trials evaluating onartuzumab in patients with solid tumors.

<p>Bev = bevacizumab, Erl = erlotinib, FOLFOX = oxaliplatin, 5-fluorouracil and folinic acid, GBM = glioblastoma, mCRC = metastatic colorectal cancer, NSCLC = non-small cell lung cancer, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed, Plat = carboplatin or cisplatin, TNBC = triple negative metastatic breast cancer. Data cut-off dates: GO27819: 7 Nov 2013; GO27820: 9 January 2014; GO27821 (Cohort 1): 31 October 2013; GO27821 (Cohort 2): 9 September 2013; GO27827: 6 Feb 2014; OAM4861g: 22 March 2014; OAM4971g: 26 October 2013; YO28252: 29 Jan 2014.</p><p>Summary of phase II/III double-blind, placebo-controlled trials evaluating onartuzumab in patients with solid tumors.</p

Frequency of low albumin (by laboratory value) in phase II and III studies evaluating onartuzumab.

<p>Bev = bevacizumab, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed.</p><p>^†Not all patients had laboratory values available. Therefore the number in each arm differs from other tables.</p><p>‡Laboratory data from studies GO27819 and OAM4861g were not available at the time of writing.</p><p>Frequency of low albumin (by laboratory value) in phase II and III studies evaluating onartuzumab.</p

Frequency of arterial thromboembolism (ATE) in phase II and III studies evaluating onartuzumab.

<p>Bev = bevacizumab, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed.</p><p>*Study OAM4861g had 3 arms: Ona + Bev + Pac (n = 62); Ona + Pbo + Pac (n = 58); Pbo + Bev + Pac (n = 62), referred to here as the control arm.</p><p>Frequency of arterial thromboembolism (ATE) in phase II and III studies evaluating onartuzumab.</p

Proportions of patients with edema and/or low albumin in studies GO27827 and OAM4971g.

<p>Values: N (%)</p><p>Proportions of patients with edema and/or low albumin in studies GO27827 and OAM4971g.</p

Frequency of gastrointestinal (GI) perforation in phase II and III studies evaluating onartuzumab.

<p>Bev = bevacizumab, Ona = onartuzumab, Pac = paclitaxel, Pbo = placebo, Pem = pemetrexed.</p><p>*Study OAM4861g had 3 arms: Ona + Bev + Pac (n = 62); Ona + Pbo + Pac (n = 58); Pbo + Bev + Pac (n = 62), referred to here as the control arm.</p><p>Frequency of gastrointestinal (GI) perforation in phase II and III studies evaluating onartuzumab.</p