A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors

A J Wagner, H Kindler, H Gelderblom, P Schöffski, S Bauer, P Hohenberger, H-G Kopp, J A Lopez-Martin, M Peeters, P Reichardt, A Qin, J Nippgen, R L Ilaria, P Rutkowski, A J Wagner, H Kindler, H Gelderblom, P Schöffski, S Bauer, P Hohenberger, H-G Kopp, J A Lopez-Martin, M Peeters, P Reichardt, A Qin, J Nippgen, R L Ilaria, P Rutkowski

Abstract

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively).

Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety.

Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension).

Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype.

Clinicaltrials.gov identifier: NCT01316263.

Keywords: IMC-3G3; gastrointestinal stromal tumor; monoclonal antibody; mutation; platelet-derived growth factor receptor α.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

References

    1. Heinrich MC, Maki RG, Corless CL. et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008; 26(33): 5352–5359.
    1. Heinrich MC, Owzar K, Corless CL. et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26(33): 5360–5367.
    1. Biron P, Cassier PA, Fumagalli E. et al. Outcome of patients (pts) with PDGFRAD842V mutant gastrointestinal stromal tumor (GIST) treated with imatinib (IM) for advanced disease. J Clin Oncol 2010; 28(Suppl 15): abstract 10051.
    1. Demetri GD, van Oosterom AT, Garrett CR. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368(9544): 1329–1338.
    1. Demetri GD, Reichardt P, Kang YK. et al. GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013; 381(9863): 295–302.
    1. Cassier PA, Fumagalli E, Rutkowski P. et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012; 18(16): 4458–4464.
    1. Heinrich MC, Corless CL, Duensing A. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299(5607): 708–710.
    1. Kang HJ, Nam SW, Kim H. et al. Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene 2005; 24(6): 1066–1074.
    1. Loizos N, Xu Y, Huber J. et al. Targeting the platelet-derived growth factor receptor α with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target. Mol Cancer Ther 2005; 4(3): 369–379.
    1. Dolloff NG, Russell MR, Loizos N, Fatatis A.. Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor. Cancer Res 2007; 67(2): 555–562.
    1. Chiorean EG, Sweeney C, Youssoufian H. et al. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol 2014; 73(3): 595–604.
    1. Wozniak A, Rutkowski P, Schöffski P. et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a European multicenter analysis based on ConticaGIST. Clin Cancer Res 2014; 20(23): 6105–6116.
    1. Wozniak A, Rutkowski P, Piskorz A. et al. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol 2012; 23(2): 353–360.
    1. Debiec-Rychter M, Sciot R, Le Cesne A. et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42(8): 1093–1103.

Source: PubMed

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