Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC)

Sylvie Lorenzen, Jorge Riera Knorrenschild, Claudia Pauligk, Susanna Hegewisch-Becker, Jörg Seraphin, Peter Thuss-Patience, Hans-Georg Kopp, Tobias Dechow, Arndt Vogel, Kim Barbara Luley, Daniel Pink, Michael Stahl, Frank Kullmann, Holger Hebart, Jens Siveke, Matthias Egger, Nils Homann, Stephan Probst, Thorsten Oliver Goetze, Salah-Eddin Al-Batran, Sylvie Lorenzen, Jorge Riera Knorrenschild, Claudia Pauligk, Susanna Hegewisch-Becker, Jörg Seraphin, Peter Thuss-Patience, Hans-Georg Kopp, Tobias Dechow, Arndt Vogel, Kim Barbara Luley, Daniel Pink, Michael Stahl, Frank Kullmann, Holger Hebart, Jens Siveke, Matthias Egger, Nils Homann, Stephan Probst, Thorsten Oliver Goetze, Salah-Eddin Al-Batran

Abstract

The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2 ) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1-d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression-free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3-5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.

Keywords: advanced gastroesophageal cancer; everolimus; paclitaxel; second-line.

© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

References

REFERENCES

    1. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000;50(1):7-33.
    1. Howlander N, Noone AM; Krapcho M, et al. SEER Cancer Statistics Review 1975-2008. http://seercancergov/csr/1975_2008. 2008.
    1. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer-a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47(15):2306-2314.
    1. Ford HE, Marshall A, Bridgewater JA, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15(1):78-86.
    1. Kang JH, Lee SI, Lim DH, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30(13):1513-1518.
    1. Hironaka S, Ueda S, Yasui H, et al. 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. 2013;31(35):4438-4444.
    1. Wilke H, Muro K, Van Cutsem E, et al. 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. Lancet Oncol. 2014;15(11):1224-1235.
    1. Oki E, Baba H, Tokunaga E, et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005;117(3):376-380.
    1. Lang SA, Gaumann A, Koehl GE, et al. Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer. 2007;120(8):1803-1810.
    1. Xu DZ, Geng QR, Tian Y, et al. Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. BMC Cancer. 2010;10:536.
    1. Yu G, Wang J, Chen Y, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15(5):1821-1829.
    1. An JY, Kim KM, Choi MG, et al. Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer. 2010;126(12):2904-2913.
    1. Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31(31):3935-3943.
    1. Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2006;9(1):14-18.
    1. Cascinu S, Graziano F, Cardarelli N, et al. Phase II study of paclitaxel in pretreated advanced gastric cancer. Anticancer Drugs. 1998;9(4):307-310.
    1. Kodera Y, Ito S, Mochizuki Y, et al. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric Cancer (CCOG0302 study). Anticancer Res. 2007;27(4C):2667-2671.
    1. Andre F, Campone M, O'Regan R, et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol. 2010;28(34):5110-5115.
    1. Shen YC, Li CP, Yen CJ, et al. Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer. Oncology. 2014;87(2):104-113.
    1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205-216.
    1. National Cancer Institute. Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events; 2009. .
    1. Kang YK, Kang WK, di Bartolomeo M, et al. Randomized phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer who failed ≥2 prior chemotherapy regimens. Ann Oncol. 2019;30(suppl_5):v851-v934.
    1. Ando T, Hosokawa A, Kajiura S, et al. Efficacy of weekly paclitaxel in patients with advanced gastric cancer refractory to docetaxel-based chemotherapy. Gastric Cancer. 2012;15(4):427-432.
    1. Maeda S, Saikawa Y, Kubota T, et al. No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay. Anticancer Res. 2003;23(4):3147-3150.
    1. Imai H, Komine K, Takahashi S, et al. Efficacy and safety assessment of paclitaxel in patients with docetaxel-resistant Esophageal squamous cell carcinoma. Chemotherapy. 2016;61(5):262-268.
    1. Sonpavde G, Pond GR, Mullane S, et al. Incomplete cross-resistance between Taxanes for advanced urothelial carcinoma: implications for clinical practice and trial design. Clin Genitourin Cancer. 2015;13(3):250-256.
    1. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39.
    1. Hurvitz SA, Dalenc F, Campone M, et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat. 2013;141(3):437-446.
    1. Chen D, Lin X, Zhang C, et al. Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway. Cell Death Dis. 2018;9(2):123.
    1. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948-1957.

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