Phase II Trial of Sorafenib in Patients with Chemotherapy Refractory Metastatic Esophageal and Gastroesophageal (GE) Junction Cancer

Yelena Y Janjigian, Efsevia Vakiani, Geoffrey Y Ku, Jessica M Herrera, Laura H Tang, Nancy Bouvier, Agnès Viale, Nicholas D Socci, Marinela Capanu, Michael Berger, David H Ilson, Yelena Y Janjigian, Efsevia Vakiani, Geoffrey Y Ku, Jessica M Herrera, Laura H Tang, Nancy Bouvier, Agnès Viale, Nicholas D Socci, Marinela Capanu, Michael Berger, David H Ilson

Abstract

Purpose: Vascular endothelial growth factor receptor (VEGFR2) directed therapies result in a modest survival benefit for patients with advanced esophageal and gastroesophageal (GE) junction cancer. Platelet-derived growth factor receptor (PDGFR) may contribute to escape from VEGFR2 inhibition. We evaluated the efficacy of sorafenib, a broad spectrum tyrosine kinase inhibitor targeting VEGFR2 and PDGFR as well as RET and RAF1, in patients with metastatic chemotherapy refractory esophageal and GE junction cancer.

Patients and methods: This phase II trial of sorafenib 400 mg twice daily enrolled chemotherapy refractory patients with metastatic esophageal and GE junction cancer with primary endpoint of progression-free survival (PFS) rate at two months. Secondary endpoints included overall survival, objective response rate and toxicity.

Results: Among 34 patients, 8 week Kaplan-Meier estimated PFS was 61% (90%CI 45 to 73%). Median PFS is 3.6 months (95% CI 1.8 to 3.9 months), with median overall survival OS 9.7 months (95% CI 5.9 to 11.6 months). Grade 3 toxicities were uncommon and included hand foot skin reaction, rash, dehydration and fatigue. One patient (3%) with ongoing complete response and remains on trial for over 5 years. Whole exome sequencing of this tumor revealed mutations in many cancer-associated genes including ARID1A, PIK3CA, and TP53, and focal amplifications of HMGA2 and MET.

Conclusion: Sorafenib therapy results in disease stabilization and encouraging PFS in patients with refractory esophageal and GE junction cancer.

Trial registration: ClinicalTrials.gov NCT00917462.

Conflict of interest statement

Competing Interests: YYJ and DHI received research funding from Bayer. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Patient enrollment and participation flow…
Fig 1. Patient enrollment and participation flow chart.
Fig 2. Waterfall plot showing maximum percentage…
Fig 2. Waterfall plot showing maximum percentage change from baseline in size of tumors in patients who received sorafenib.
Data available for 33 patients, one patient did not have a CT due to rapid clinical deterioration. Numbers on the bars indicate months on sorafenib, the bars without numbers indicate patients who progressed on the study rapidly within

Fig 3. Kaplan-Meier Survival.

A. Kaplan-Meier curve…

Fig 3. Kaplan-Meier Survival.

A. Kaplan-Meier curve showing PFS in patients who received sorafenib. B.…

Fig 3. Kaplan-Meier Survival.
A. Kaplan-Meier curve showing PFS in patients who received sorafenib. B. Kaplan-Meier curve showing OS in patients who received sorafenib.
Fig 3. Kaplan-Meier Survival.
Fig 3. Kaplan-Meier Survival.
A. Kaplan-Meier curve showing PFS in patients who received sorafenib. B. Kaplan-Meier curve showing OS in patients who received sorafenib.

References

    1. Bass AJ, Thorsson V, Shmulevich I, Reynolds SM, Miller M, Bernard B, et al. (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513: 202–209. 10.1038/nature13480
    1. Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, et al. (2009) Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer. PLoS Genet 5: e1000676 10.1371/journal.pgen.1000676
    1. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29: 15–18.
    1. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet 383: 31–39.
    1. Qin S, P L A Cancer Center of Nanjing Bayi Hospital, Nanjing, China. Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial.; 2014. J Clin Oncol 32:5s, 2014 (suppl; abstr 4003).
    1. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes H-P, et al. (2003) Combined inhibition of VEGF- and PDGF-signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. The FASEB Journal.
    1. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, et al. (2007) Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels. Cell 131: 463–475.
    1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotech 29: 1039–1045.
    1. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5: 835–844.
    1. Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson AB 3rd (2010) Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 28: 2947–2951. 10.1200/JCO.2009.27.7988
    1. Chong H, Vikis HG, Guan K-L (2003) Mechanisms of regulating the Raf kinase family. Cellular Signalling 15: 463–469.
    1. Tew W, Shah M, Schwartz G, Kelsen D, Ilson D (2005) Phase II trial of erlotonib for second-line treatment in advanced esophageal cancer. In: Proc GI ASCO; 2005, vol 5 abstr.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. (2000) New Guidelines to Evaluate the Response to Treatment in Solid Tumors. Journal of the National Cancer Institute 92: 205–216.
    1. Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. (2013) Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 31: 4438–4444. 10.1200/JCO.2012.48.5805
    1. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. (2006) Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group. pp. 4991–4997.
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. (2008) Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of Medicine 359: 378–390. 10.1056/NEJMoa0708857
    1. Connell C, O'Reilly S, Webb G, Moulton B, Parker I, McDermott R, et al. ICORG 06–41: A phase II trial of single-agent sorafenib in the treatment of platinum-pretreated relapsed gastroesophageal adenocarcinoma (GECa). 2014.
    1. Martin-Richard M, Gallego R, Pericay C, Foncillas JG, Queralt B, Casado E, et al. (2013) Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A gemcad study. Investigational New Drugs 31: 1573–1579.
    1. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338: 221 10.1126/science.1226344
    1. . Accessed: . The trial number is .
    1. Imielinski M, Greulich H, Kaplan B, Araujo L, Amann J, Horn L, et al. (2014) Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma. The Journal of Clinical Investigation 124: 1582–1586. 10.1172/JCI72763
    1. Wilke H, Muro K, Van Cutsem E, Oh S-C, Bodoky G, Shimada Y, et al. (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. The Lancet Oncology 15: 1224–1235. 10.1016/S1470-2045(14)70420-6
    1. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. (2011) Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study. Journal of Clinical Oncology 29: 3968–3976. 10.1200/JCO.2011.36.2236
    1. Yoon H, Bendell J, Braiteh F, Firdaus I, Philip P, Cohn A, et al. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial. J Clin Oncol 32:5s, 2014. (suppl; abstr 4004).
    1. Van Cutsem E, de Haas S, Kang Y-K, Ohtsu A, Tebbutt NC, Ming Xu J, et al. (2012) Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Biomarker Evaluation From the AVAGAST Randomized Phase III Trial. Journal of Clinical Oncology 30: 2119–2127. 10.1200/JCO.2011.39.9824
    1. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet.
    1. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6: 327–338. 10.1038/nrclinonc.2009.63
    1. Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, et al. (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet 381: 303–312.
    1. Demetri GD, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, Gelderblom H, et al. (2013) 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. The Lancet 381: 295–302.
    1. Pavlakis N, Sjoquist KM, Tsobanis E, Martin AJ, Kang Y-K, Bang Y-J, et al. (2015) LBA-06INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib (REG) in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG): Final overall and subgroup results. Annals of Oncology 26: iv119.

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