|Ahead of print
The efficacy and safety of onartuzumab in patients with solid cancers: A meta-analysis of randomized trials
Bum Jun Kim1, Dalyong Kim2, Jung Han Kim1, Hyeong Su Kim1, Hyun Joo Jang1
1 Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea
2 Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
|Date of Submission||10-Dec-2018|
|Date of Decision||06-Jun-2019|
|Date of Acceptance||15-Jun-2019|
|Date of Web Publication||02-Nov-2020|
Hyun Joo Jang,
Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul
Republic of Korea
Source of Support: None, Conflict of Interest: None
Background: Onartuzumab, a humanized monovalent monoclonal antibody to the MET protein, has been tested in various cancers. We conducted a meta-analysis of randomized phase II and III clinical trials to investigate the efficacy and safety of onartuzumab in solid cancers.
Methods: We searched PubMed, PMC, EMBASE, and the Cochrane library databases. We included randomized phase II or III trials that evaluated the additional benefits of onartuzumab in comparison with the standard treatments. Data on progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were pooled and analyzed.
Results: From nine studies, a total of 2,138 patients were included in the meta-analysis. The addition of onartuzumab to the standard treatment resulted in no improvement of PFS (hazard ratio (HR) = 1.00 [95% confidence interval (CI), 0.90–1.11], P = 0.93) and OS (HR = 1.08 [95% CI, 0.94–1.23], P = 0.29). In the subgroup analysis with patients with non-small-cell lung cancer (NSCLC), onartuzumab was not associated with a significant improvement of OS (HR = 1.12 [95% CI, 0.93–1.34], P = 0.23) and PFS (HR = 1.05 [95% CI, 0.91–1.21], P = 0.52). With respect to AEs, onartuzumab increased the incidence of hypoalbuminemia (odds ratio (OR) = 14.8 [95% CI, 3.49–62.71], P < 0.001), peripheral edema (OR = 6.52 [95% CI, 3.60–11.81], P < 0.001), neutropenia (OR = 1.36 [95% CI, 1.03–1.79], P = 0.03), thrombocytopenia (OR = 1.98 [95% CI, 1.03–3.81], P = 0.04), and venous thrombotic events (OR = 3.05 [95% CI, 1.39–6.71], P = 0.006).
Conclusion: This meta-analysis indicates that the addition of onartuzumab to the standard treatments had no definite survival benefit with increased severe toxicities in patients with solid cancer.
Keywords: Anti-MET inhibitor, meta-analysis, onartuzumab, review
Key Message The addition of onartuzumab to the standard anticancer treatments had no survival benefit in patients with solid cancer.
|How to cite this URL:|
Kim BJ, Kim D, Kim JH, Kim HS, Jang HJ. The efficacy and safety of onartuzumab in patients with solid cancers: A meta-analysis of randomized trials. Indian J Cancer [Epub ahead of print] [cited 2021 Feb 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=299724
Bum Jun Kim and Dalyong Kim equally contributed to this work.
| » Introduction|| |
The mesenchymal-epithelial transition (MET) is a cell membrane receptor activated by hepatocyte growth factor (HGF). Signaling through HGF/MET stimulates wound healing and tissue repair in normal tissue but can promote proliferation, survival, and metastasis in tumor cells., Aberrant MET signaling can be driven by multiple mechanisms, particularly the overexpression of MET, with or without gene amplification and is considered to be an important oncogenic factor in several human malignancies.
Previous studies have shown that MET was overexpressed or amplified in various solid cancers., MET overexpression has been reported to correlate with aggressive biological tumor characteristics, poor prognosis, and a greater incidence of metastases,, and has been investigated as a potential therapeutic target for anti-cancer treatment.,
Onartuzumab is a recombinant, fully humanized, monovalent, anti-MET monoclonal antibody against the extracellular domain of the MET tyrosine kinase receptor. By binding with MET, onartuzumab prevents MET from binding with HGF and inhibits the HGF/MET signaling pathway, which has an important role in tumorigenesis.
After the preclinical rationale was established, a phase II study of onartuzumab was conducted in patients with non-small-cell lung cancer (NSCLC). The results revealed that second/third-line onartuzumab in combination with erlotinib improved progression-free survival (PFS) and overall survival (OS) compared with erlotinib plus placebo in the MET-positive subgroup. The promising results from this phase II trial encouraged the investigators to conduct several randomized phase II or III clinical trials in various solid cancers, and the results of these trials have recently been published.
We conducted this meta-analysis of randomized phase II and III clinical trials to obtain comprehensive results on the efficacy and safety of onartuzumab for the treatment of solid cancers.
| » Materials and Methods|| |
The current study was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.
To identify potentially relevant articles, we searched the PubMed, PMC, EMBASE, and Cochrane library databases for articles published up to May 2019 that included the following medical terms in their titles, abstracts, or keyword lists: “onartuzumab,” “randomized,” and “carcinoma or malignant neoplasm or solid cancer.” Abstracts presented at the American Society of Clinical Oncology (ASCO) (2012–2019) and the European Society for Medical Oncology (ESMO) (2012–2018) were also searched for relevant clinical trials. All eligible studies were retrieved and their bibliographies were checked for other relevant publications.
Eligible studies meeting all the following criteria were included in our analysis: studies that were prospectively randomized controlled phase II or III trials conducted in patients with solid cancer; studies involving randomization of patients to treatment with either standard treatment or onartuzumab in combination with standard treatment; studies providing the hazard ratio (HR) and its 95% confidence interval (CI) for PFS or OS; studies providing the odds ratio (OR) and its 95% CI for the incidence of adverse events (AEs). If HR or OR with their 95% CIs could be calculated from the data provided, such studies were also eligible for our analysis. The languages and years in which studies were published did not serve as the limiting factors.
All data were independently extracted by two authors (BJ Kim and D Kim). If these two authors did not agree, the principal investigator (JH Kim) was consulted to resolve the discrepancies. The following information was collected from each study, although some studies did not contain all the information: the first author's name, year of publication, trial phase, treatment setting, number of participants, treatment regimens, PFS, and its HR with 95% CI, OS, and its HR with 95% CI, and the incidence of AEs of interest and their ORs with 95% CI.
The methodological quality of the included studies was scored using the Jadad 5-item scale, considering randomization, double blinding, and withdrawals. The final score ranged from 0 to 5, with low-quality studies having a score ≤2 and high-quality studies having a score of ≥3.
The statistical values used in the analysis were obtained directly or indirectly from the original article. The heterogeneity across studies was estimated by using the I2 inconsistency test and Chi-square-based Cochran's Q statistic test in which P < 0.1 and I2 > 50% was taken to indicate the presence of significant heterogeneity. The fixed-effect model (Mantel-Haenszel method) was used to calculate the pooled HR and the pooled OR when substantial heterogeneity was not observed. When substantial heterogeneity was observed, we carried out additional subgroup analyses to identify the source of heterogeneity and applied the random-effect model (DerSimonian-Laird method) for the analysis. The RevMan (version 5.2) was used to combine the data. The sensitivity analysis was performed to detect the influence individual trial on the pooled results: this involved the removal of one trial each time. A funnel plot was used to test publication bias. For the quantitative analysis of publication bias, Begg's test and Egger's test were performed using the statistical software packages R (www.r-project.org)., All reported P values were two-sided and P < 0.05 was considered statistically significant.
Because the meta-analysis did not involve studies with human or animal subjects performed by any of the authors, this study received a waiver for review by the ethical committee.
| » Results|| |
Results of search
The flowchart of studies to describe the studies through the selection process is shown in [Figure 1]. Fifty-four potentially relevant studies were identified and screened by the search strategy; 37 studies were excluded after the screening of the titles and abstracts. Of the remaining 18 potentially relevant prospective studies, nine studies were further excluded for not satisfying the inclusion criteria. Finally, seven randomized phase II trials,,,,,, and two randomized phase III trials, were included in the meta-analysis.
Characteristics of the eligible studies
The characteristics and statistical values of the included studies are summarized in [Table 1]. Among the nine included studies, four studies were conducted in NSCLC patients and two in gastroesophageal cancer. Of the remaining three studies, there was one each in colorectal cancer, glioblastoma, and triple negative breast cancer. One study of patients with NSCLC was conducted in two different cohorts, and each study was considered an independent study. All the studies had Jadad score of 5, suggesting good quality of each trial.
A total of 2,138 patients in nine studies were included in the efficacy and safety analysis. Subgroup data according to the MET status were provided in seven studies.,,,,,, MET status was determined by immunohistochemistry, and MET positivity was defined when ≥ 50% of tumor cells were stained positive with an intensity of 2 or greater.
The meta-analysis did not identify any additional benefit of onartuzumab with respect to OS compared to standard treatment (HR = 1.08 [95% CI, 0.94–1.23], P = 0.29, I2 = 0%) [Figure 2]a. However, subgroup analysis according to the MET status revealed that onartuzumab significantly prolonged OS in MET positive patients (HR = 0.72 [95% CI, 0.54–0.95], P = 0.02, I2 = 47%) [Figure 2]b.
|Figure 2: Forest plots of hazard ratios comparing overall survival with or without onartuzumab in intention-to-treat population (a) and MET-positive population (b). Funnel plots for publication bias in intention-to-treat population (c) and MET-positive population (d)|
Click here to view
In the PFS analysis, onartuzumab was not associated with improved PFS (HR = 1.00 [95% CI, 0.90–1.11], P = 0.93, I2 = 0%) [Figure 3]a, and the same result was observed in the MET positive sub-population (HR = 1.00 [95% CI, 0.87–1.16], P = 0.98, I2 = 34%) [Figure 3]b.
|Figure 3: Forest plots of hazard ratios comparing progression-free survival with or without onartuzumab in intention-to-treat population (a) and MET-positive population (b). Funnel plots for publication bias in intention-to-treat population (c) and MET-positive population (d)|
Click here to view
Subgroup analysis for NSCLC
We performed a subgroup analysis for patients with NSCLC. Onartuzumab was not associated with prolonged OS (HR = 1.12 [95% CI, 0.93-1.34], P = 0.23, I2 = 0%) [Figure 4]a and PFS (HR = 1.05 [95% CI, 0.91–1.21], P = 0.52, I2 = 0%) [Figure 4]b in patients with NSCLC. In patients with MET-positive NSCLC, PFS was not improved with onartuzumab (HR = 1.07 [95% CI, 0.79–1.46], P = 0.66, I2 = 52%). We adopted random-effects model because there was significant heterogeneity.
|Figure 4: Forest plots of hazard ratios comparing overall survival (a) and progression-free survival (b) with or without onartuzumab in NSCLC patients. Funnel plots for publication bias regarding overall survival (c) and progression-free survival (d)|
Click here to view
To evaluate the safety of onartuzumab in combination with standard treatment, we calculated ORs and their 95% CIs of ≥ grade 3 AEs from each study. The dose of onartuzumab was equal at 15 mg/kg every 3 weeks in all studies. The list of common AEs and AEs of special interests is shown in [Table 2]. Onartuzumab was shown to increase hypoalbuminemia (OR = 14.8 [95% CI, 3.49–62.71], P < 0.001, I2 = 0%), peripheral edema (OR = 6.52 [95% CI, 3.60–11.81], P < 0.001, I2 = 0%), neutropenia (OR = 1.36 [95% CI, 1.03–1.79], P = 0.03, I2 = 9%), and thrombocytopenia (OR = 1.98 [95% CI, 1.03–3.81], P = 0.04, I2 = 47%) with statistical significance. Among AEs with special interest, venous thrombotic events were significantly higher in the patients who received onartuzumab (OR = 3.05 [95% CI, 1.39–6.71], P = 0.006, I2 = 0%).
We used a funnel plot to access the publication bias and performed Egger's and Begg's test for its quantification. The results showed that there was no evidence of publication bias in both the efficacy and safety analyses [Figure 2]c, 2d, 3c, 3d, 4c and 4d].
| » Discussion|| |
We conducted this study to investigate the efficacy and safety of onartuzumab in solid cancers. This meta-analysis of randomized phase II or III trials revealed that the addition of onartuzumab to standard treatment was not associated with survival benefits.
The meta-analysis of nine relevant studies revealed that onartuzumab failed to show longer PFS or OS in patients with solid cancers (HR = 1.08, P = 0.29). With respect to AEs, onartuzumab significantly increased hypoalbuminemia (OR = 14.8, P < 0.001), peripheral edema (OR = 6.52, P < 0.001), neutropenia (OR = 1.36, P = 0.03), thrombocytopenia (OR = 1.98, P = 0.04), and venous thrombotic events (OR = 3.05, P = 0.006). In the subgroup analysis with patients with NSCLC, onartuzumab was not associated with prolonged OS (HR = 1.12, P = 0.23) and PFS (HR = 1.05, P = 0.52). Subgroup analysis according to the MET status showed that onartuzumab conferred an additional survival benefit (HR = 0.72, P = 0.02) in MET-positive population. As a limited number of studies were included (only five) and they possessed a considerable heterogeneity (I2 = 47%), however, this finding may not be sufficient to determine the survival benefit of onartuzumab in patients with MET-positive cancer. The initial phase II study with positive results seemed to have a decisive impact on this outcome. In the sensitivity analysis, our positive result lost its statistical significance after the removal of this successful study (HR = 0.83, P = 0.26).
Several reasons may explain these negative results. The most plausible explanation for this failure is that MET overexpression might not be an appropriate target for onartuzumab in solid cancers. Although MET overexpression is the most common type of aberrant MET/HGF signaling, dysregulation of the MET signaling pathway can also be induced from other mechanisms, including MET amplification and rare MET mutations affecting the extracellular domain, the tyrosine kinase domain, or the juxtamembrane domain. Another hypothesis is that inappropriate MET signaling may be a consequence, rather than the cause, of the cell transformation: therefore, targeting MET signaling would not fundamentally affect tumor behavior or cancer outcomes. On the assumption that aberrant MET signaling is a mid-step in a course of cell transformation, targeting the MET pathway for control of signal transduction in cancers may be an inefficient strategy, requiring multiple points of the blockade. Therefore, only blocking the extracellular domain of the MET tyrosine kinase receptor by anti-MET monoclonal antibody in the tumors harboring MET overexpression as a late event would probably not confer large survival benefits. The emerging data have suggested that splice-site mutations (MET exon 14) or a high level of MET amplification led to significant response to MET inhibitors.,,,,, Thus, MET mutation or true amplification may represent a better way to select patients for MET inhibitors, especially MET tyrosine kinase inhibitors.
This study has a couple of major limitations that should be noted. First, the meta-analysis included a small number of studies. Second, the patients had different tumor types and received different therapeutic regimens in various treatment settings ( first-line or salvage setting).
In conclusion, this meta-analysis of randomized phase II or III trials failed to identify significant survival benefits of onartuzumab in solid cancers. These results suggest that MET inhibition using ligand-blocking antibodies may not be suitable for targeting HGF/MET dysregulation. Translational studies to explore more specific biomarkers are needed to identify ideal candidates for MET inhibitors
This work had no specific funding support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ma PC, Maulik G, Christensen J, Salgia R. c-Met: Structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003;22:309-25.
Blumenschein GR, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012;30:3287-96.
Trusolino L, Bertotti A, Comoglio PM. MET signalling: Principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 2010;11:834-48.
Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S,et al
. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 2008;47:1025-37.
Zhang H, Bao Z, Liao H, Li W, Chen Z, Shen H, Ying S. The efficacy and safety of tivantinib in the treatment of solid tumors: Asystematic review and meta-analysis. Oncotarget 2017;8:113153-62.
Finocchiaro G, Toschi L, Gianoncelli L, Baretti M, Santoro A. Prognostic and predictive value of MET deregulation in non-small cell lung cancer. Ann Transl Med 2015;3:83.
Pérez-Vargas JCS, Biondani P, Maggi C, Gariboldi M, Gloghini A, Inno A, et al
. Role of cMET in the development and progression of colorectal cancer. Int J Mol Sci 2013;14:18056-77.
Park J, Choi Y, Ko YS, Kim Y, Pyo JS, Jang BG, et al
. FOXO1 Suppression is a determinant of acquired lapatinib-resistance in HER2-positive gastric cancer cells through MET upregulation. Cancer Res Treat 2018;50:239-54.
Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M, et al
. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. ProcNatlAcadSci USA 2013;110:E2987-96.
Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA, et al
. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 2005;65:1479-88.
Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH, Blumenschein GR,et al
. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013;31:4105-14.
Panic N, Leoncini E, de Belvis G, Ricciardi W, Boccia S. Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One 2013;8:e83138.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al
. Assessing the quality of reports of randomized clinical trials: Isblinding necessary? Control Clin Trials 1996;17:1-12.
Eagger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected 3y a simple graphical test. BMJ 1997;315:629-34.
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al
. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.
Hirsch FR, Govindan R, Zvirbule Z, Braiteh F, Rittmeyer A, Belda-Iniesta C, et al
. Efficacy and safety results from a phase II, placebo-controlled study of onartuzumabplus first-line platinum-doublet chemotherapy for advanced squamous cell non-small-cell lung cancer. Clin Lung Cancer 2017;18:43-9.
Wakelee H, Zvirbule Z, De Braud F, Kingsley CD, Mekhail T, Lowe T, et al
. Efficacy and safety of onartuzumab in combination with first-line bevacizumab- or pemetrexed-based chemotherapy regimens in advanced non-squamous non-small-cell lung cancer. Clin Lung Cancer 2017;18:50-9.
Shah MA, Cho JY, Tan IB, Tebbutt NC, Yen CJ, Kang A, et al
. A randomized phase II study of FOLFOX with or without the MET inhibitor onartuzumab in advanced adenocarcinoma of the stomach and gastroesophageal junction. Oncologist 2016;21:1085-90.
Bendell JC, Hochster H, Hart LL, Firdaus I, Mace JR, McFarlane JJ, et al
. A phase II randomized trial (GO27827) of first-line FOLFOX plus bevacizumab with or without the MET inhibitor onartuzumab in patients with metastatic colorectal cancer. Oncologist 2017;22:264-71.
Cloughesy T, Finocchiaro G, Belda-Iniesta C, Recht L, Brandes AA, Pineda E, et al
. Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumabplus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses. J Clin Oncol 2017;35:343-51.
Diéras V, Campone M, Yardley DA, Romieu G, Valero V, IsakoffSJ, et al
. Randomized, phase II, placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer. Ann Oncol 2015;26:1904-10.
Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, et al
. Results from the phase III randomized trial of onartuzumabplus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 2017;35:412-20.
Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, et al
. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: The METgastricrandomized clinical trial. JAMAOncol 2017;3:620-7.
Pérol M. Negative results of METLung study: An opportunity to better understand the role of MET pathway in advanced NSCLC. Transl Lung Cancer Res 2014;3:392-4.
Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al
. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842-9.
Noonan SA, Berry L, Lu X, Gao D, Barón AE, Chesnut P, et al
. Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J Thorac Oncol 2016;11:1293-304.
Kawakami H, Okamoto I, Okamoto W, Tanizaki J, Nakagawa K, Nishio K. Targeting MET amplification as a new oncogenic driver. Cancers (Basel) 2014;6:1540-52.
Camidge DR, Ou S-HI, Shapiro G, Otterson GA, Villaruz LC, Villalona-Calero MA,et al
. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32(Suppl 15):8001.
Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X, Bauer TM, et al
. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015;5:850-9.
Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, et al
. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol 2016;34:721-30.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]