Investigational New Drugs

, Volume 37, Issue 6, pp 1239–1246 | Cite as

A multicenter, prospective phase II trial of gemcitabine plus axitinib in patients with renal cell carcinoma with a predominant sarcomatoid component

  • Inkeun Park
  • Hyo Jin Lee
  • Woo Kyoon Bae
  • Shinkyo Yoon
  • Jae Lyun LeeEmail author


Introduction We conducted a multicenter, phase 2 trial using gemcitabine plus axitinib (GX) in patients with recurrent or metastatic sarcomatoid renal cell carcinoma (SRCC) to evaluate its efficacy and safety. Methods Patients with advanced RCC and a sarcomatoid component of ≥25% on resected kidney or exclusive sarcomatoid carcinoma on needle biopsy were included. Patients received gemcitabine 1000 mg/m2 intravenously on days 1 and 8 of a 3-week cycle and axitinib 5 mg twice daily. Primary endpoint was objective response rate (ORR) according to the response evaluation criteria in solid tumors version 1.1, and secondary end points were progression-free (PFS) and overall (OS) survivals and adverse events. Results Twenty-five patients were enrolled. Median age was 61 (range: 33–80), and 84% were men. The Eastern Cooperative Oncology Group performance status was one in 23 patients (92%). Clear cell carcinoma was the most common histology of the carcinoma component (60%). ORR was 56%, and 28% patients achieved stable disease with a control rate of 84%. With a median follow-up duration of 24.8 months, the median PFS was 4.2 months (95% CI, 2.3–6.1) and median OS was 8.4 months (95% CI 3.3–13.4 months). The most common grade 3 or higher adverse events were neutropenia (36%), hypertension (12%), and anorexia (12%). Most adverse events were manageable, and no unexpected toxicities were found. Conclusion GX showed promising efficacy in patients with SRCC. GX could be considered as a treatment option for patients with SRCC and should be confirmed in larger clinical trials.


Renal cell carcinoma Sarcomatoid Gemcitabine Axitinib Chemotherapy 



We thank Pfizer Korea and the Chong Kun Dang Pharmaceutical Corporation for their kind donation of axitinib and gemcitabine, respectively. This study was presented in part during the Genitourinary Cancers Symposium, 14-16 February 2019, in San Francisco, CA.

Compliance and ethical standards

Conflict of interest

Inkeun Park received honoraria for consulting or advisory roles from Pfizer Korea, Eisai Korea, Bristol-Myers Squibb pharma Korea, Astellas Pharma Korea, Janssen Korea, and iPSEN Korea. Jae Lyun Lee received honoraria for consulting or advisory roles from Pfizer Korea, Eisai Korea, Sanofi-Aventis Korea, Bristol-Myers Squibb Korea, Astellas Pharma, and Amgen Korea, and his institution received research funds from Pfizer, grants from Janssen, grants from Novartis, grants from Bristol-Myers Squibb, grants from Reche/Genentech, grants from AstraZeneca/MedImmune, grants from MSD.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

This study was approved by the institutional review board of each participating centers and Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Sella A, Logothetis CJ, Ro JY, Swanson DA, Samuels ML (1987) Sarcomatoid renal cell carcinoma. A treatable entity. Cancer 60:1313–1318CrossRefGoogle Scholar
  2. 2.
    Cangiano T, Liao J, Naitoh J, Dorey F, Figlin R, Belldegrun A (1999) Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy. J Clin Oncol 17:523–528CrossRefGoogle Scholar
  3. 3.
    Shuch B, Said J, LaRochelle JC, Zhou Y, Li G, Klatte T, Pouliot F, Kabbinavar FF, Belldegrun AS, Pantuck AJ (2010) Histologic evaluation of metastases in renal cell carcinoma with sarcomatoid transformation and its implications for systemic therapy. Cancer 116:616–624. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lohse CM, Cheville JC (2005) A review of prognostic pathologic features and algorithms for patients treated surgically for renal cell carcinoma. Clin Lab Med 25:433–464. CrossRefPubMedGoogle Scholar
  5. 5.
    Golshayan AR, George S, Heng DY, Elson P, Wood LS, Mekhail TM, Garcia JA, Aydin H, Zhou M, Bukowski RM, Rini BI (2009) Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. J Clin Oncol 27:235–241. CrossRefPubMedGoogle Scholar
  6. 6.
    Bangalore N, Bhargava P, Hawkins MJ, Bhargava P (2001) Sustained response of sarcomatoid renal-cell carcinoma to MAID chemotherapy: case report and review of the literature. Ann Oncol 12:271–274CrossRefGoogle Scholar
  7. 7.
    Dutcher JP, Nanus D (2011) Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. Med Oncol 28:1530–1533. CrossRefPubMedGoogle Scholar
  8. 8.
    Fujiwara Y, Kiura K, Tabata M, Takigawa N, Hotta K, Umemura S, Omori M, Gemba K, Ueoka H, Tanimoto M (2008) Remarkable shrinkage of sarcomatoid renal cell carcinoma with single-agent gemcitabine. Anti-Cancer Drugs 19:431–433. CrossRefPubMedGoogle Scholar
  9. 9.
    Nanus DM, Garino A, Milowsky MI, Larkin M, Dutcher JP (2004) Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 101:1545–1551. CrossRefPubMedGoogle Scholar
  10. 10.
    Escudier B, Droz JP, Rolland F, Terrier-Lacombe MJ, Gravis G, Beuzeboc P, Chauvet B, Chevreau C, Eymard JC, Lesimple T, Merrouche Y, Oudard S, Priou F, Guillemare C, Gourgou S, Culine S, Genitourinary Group of the French Federation of Cancer C (2002) Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 168:959–961. CrossRefPubMedGoogle Scholar
  11. 11.
    Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J (2011) A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 29:761–767. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Park I, Cho YM, Lee JL, Ahn JH, Lee DH, Song C, Hong JH, Kim CS, Ahn H (2013) Prognostic factors of metastatic renal cell carcinoma with extensive sarcomatoid component. J Cancer Res Clin Oncol 139:817–827. CrossRefPubMedGoogle Scholar
  13. 13.
    Beuselinck B, Lerut E, Wolter P, Dumez H, Berkers J, Van Poppel H, Joniau S, Oyen R, De Wever L, Strijbos M, Paridaens R, Schoffski P (2014) Sarcomatoid dedifferentiation in metastatic clear cell renal cell carcinoma and outcome on treatment with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors: a retrospective analysis. Clin Genitourin Cancer 12:e205–e214. CrossRefPubMedGoogle Scholar
  14. 14.
    Molina AM, Tickoo SK, Ishill N, Trinos MJ, Schwartz LH, Patil S, Feldman DR, Reuter VE, Russo P, Motzer RJ (2011) Sarcomatoid-variant renal cell carcinoma: treatment outcome and survival in advanced disease. Am J Clin Oncol 34:454–459. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kunene V, Miscoria M, Pirrie S, Islam MR, Afshar MPorfiri E (2014) Sarcomatoid renal cell carcinoma: clinical outcome and survival after treatment with sunitinib. Clin Genitourin Cancer 12:251–255. CrossRefPubMedGoogle Scholar
  16. 16.
    Kyriakopoulos CE, Chittoria N, Choueiri TK, Kroeger N, Lee JL, Srinivas S, Knox JJ, Bjarnason GA, Ernst SD, Wood LA, Vaishampayan UN, Agarwal N, Pal SK, Kanesvaran R, Rha SY, Yuasa T, Donskov F, North SA, Heng DY, Rini BI (2015) Outcome of patients with metastatic sarcomatoid renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Clin Genitourin Cancer 13:e79–e85. CrossRefPubMedGoogle Scholar
  17. 17.
    Staehler M, Haseke N, Roosen A, Stadler T, Bader M, Siebels M, Karl A, Stief CG (2010) Sorafenib after combination therapy with gemcitabine plus doxorubicine in patients with sarcomatoid renal cell carcinoma: a prospective evaluation. Eur J Med Res 15:287–291CrossRefGoogle Scholar
  18. 18.
    Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK (2015) Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 121:3435–3443. CrossRefPubMedGoogle Scholar
  19. 19.
    Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O'Connor P, Shalinsky DR, Bender SL (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283. CrossRefPubMedGoogle Scholar
  20. 20.
    Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939. CrossRefPubMedGoogle Scholar
  21. 21.
    Konishi S, Hatakeyama S, Tanaka T, Ikehata Y, Tanaka T, Fujita N, Ishibashi Y, Yamamoto H, Yoneyama T, Hashimoto Y, Yoshikawa K, Kawaguchi T, Masumori N, Kitamura H, Ohyama C (2018) Comparison of axitinib and sunitinib as first-line therapies for metastatic renal cell carcinoma: a real-world multicenter analysis. Med Oncol 36:6. CrossRefPubMedGoogle Scholar
  22. 22.
    Park I, Lee SH, Lee JL (2018) A multicenter phase II trial of Axitinib in patients with recurrent or metastatic non-clear-cell renal cell carcinoma who had failed prior treatment with Temsirolimus. Clin Genitourin Cancer 16:e997–e1002. CrossRefPubMedGoogle Scholar
  23. 23.
    Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 12:256–262. CrossRefPubMedGoogle Scholar
  24. 24.
    Maiti A, Nemati-Shafaee M, Msaouel P, Pagliaro LC, Jonasch E, Tannir NM, Shah AY (2017) Phase 2 trial of Capecitabine, gemcitabine, and bevacizumab in Sarcomatoid renal-cell carcinoma. Clin Genitourin Cancerdoi 16:e47–e57. CrossRefGoogle Scholar
  25. 25.
    Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N, Investigators AT (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111. CrossRefPubMedGoogle Scholar
  27. 27.
    Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ (2013) Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 14:1287–1294. CrossRefPubMedGoogle Scholar
  28. 28.
    Joseph RW, Millis SZ, Carballido EM, Bryant D, Gatalica Z, Reddy S, Bryce AH, Vogelzang NJ, Stanton ML, Castle EP, Ho TH (2015) PD-1 and PD-L1 expression in renal cell carcinoma with Sarcomatoid differentiation. Cancer Immunol Res 3:1303–1307. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rini BI, Huseni M, Atkins MB, McDermott DF, Powles TB, Escudier B, Banchereau R, Liu LF, Leng N, Fan J, Doss J, Nalle S, Carroll S, Li S, Schiff C, Green M, Motzer RJ (2018) LBA31Molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): results from a phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC). Ann Oncol 29:mdy424.037–mdy424.037. CrossRefGoogle Scholar
  30. 30.
    Bi M, Zhao S, Said JW, Merino MJ, Adeniran AJ, Xie Z, Nawaf CB, Choi J, Belldegrun AS, Pantuck AJ, Kluger HM, Bilguvar K, Lifton RP, Shuch B (2016) Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci U S A 113:2170–2175. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang Z, Kim TB, Peng B, Karam J, Creighton C, Joon A, Kawakami F, Trevisan P, Jonasch E, Chow CW, Canales JR, Tamboli P, Tannir N, Wood C, Monzon F, Baggerly K, Varella-Garcia M, Czerniak B, Wistuba I, Mills G, Shaw K, Chen K, Sircar K (2017) Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile, and transcriptional landscape. Clin Cancer Res 23:6686–6696. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    El Mouallem N, Smith SC, Paul AK (2018) Complete response of a patient with metastatic Sarcomatoid renal cell carcinoma to a programmed Death-1 checkpoint inhibitor. J Oncol Pract 14:511–513. CrossRefPubMedGoogle Scholar
  33. 33.
    Geynisman DM (2015) Anti-programmed cell death protein 1 (PD-1) antibody Nivolumab leads to a dramatic and rapid response in papillary renal cell carcinoma with Sarcomatoid and Rhabdoid features. Eur Urol 68:912–914. CrossRefPubMedGoogle Scholar
  34. 34.
    Rouvinov K, Osyntsov L, Shaco-Levy R, Baram N, Ariad S, Mermershtain W (2017) Rapid response to Nivolumab in a patient with Sarcomatoid transformation of Chromophobe renal cell carcinoma. Clin Genitourin Cancer 15:e1127–e1130. CrossRefPubMedGoogle Scholar
  35. 35.
    McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, Powderly JD, Infante JR, Fasso M, Wang YV, Zou W, Hegde PS, Fine GD, Powles T (2016) Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 34:833–842. CrossRefPubMedGoogle Scholar
  36. 36.
    Malouf GG, Ali SM, Wang K, Balasubramanian S, Ross JS, Miller VA, Stephens PJ, Khayat D, Pal SK, Su X, Sircar K, Tamboli P, Jonasch E, Tannir NM, Wood CG, Karam JA (2016) Genomic characterization of renal cell carcinoma with Sarcomatoid dedifferentiation pinpoints recurrent genomic alterations. Eur Urol 70:348–357. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Inkeun Park
    • 1
  • Hyo Jin Lee
    • 2
  • Woo Kyoon Bae
    • 3
  • Shinkyo Yoon
    • 4
  • Jae Lyun Lee
    • 4
    Email author
  1. 1.Division of Medical Oncology, Department of Internal Medicine, Gil Medical CenterGachon University College of MedicineIncheonRepublic of Korea
  2. 2.Department of Internal MedicineChungnam National University School of MedicineDaejeonRepublic of Korea
  3. 3.Department of Hemato-OncologyChonnam National University Hwasun HospitalHwasunRepublic of Korea
  4. 4.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea

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