Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO)

Authors: Thomas Decker, Friedrich Overkamp, Siegfried Rösel, Arnd Nusch, Thomas Göhler, Martin Indorf, Jörg Sahlmann, Tanja Trarbach

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

We conducted an open-label, randomized, two-arm multi-center study to assess the efficacy and safety of paclitaxel versus paclitaxel + sorafenib in patients with locally advanced or metastatic HER2-negative breast cancer.

Methods

Patients were randomly assigned to receive either paclitaxel monotherapy (80 mg/m2) weekly (3 weeks on, 1 week off) plus sorafenib 400 mg orally, twice a day taken continuously throughout 28 day cycles. Sorafenib dose was gradually escalated from a starting dose of 200 mg twice a day. The primary endpoint was progression free survival (PFS).

Results

A pre-planned efficacy interim analysis was performed on the data of 60 patients, 30 patients in each treatment arm. Median PFS was estimated at 6.6 months (95% CI: 5.1 to 9.0) in patients randomized to single-agent paclitaxel (Arm A) and 5.6 months (95% CI: 3.8 to 6.5) in patients randomized to paclitaxel-sorafenib combination (Arm B) therapy. Contrary to the hypothesis, the treatment effect was statistically significant in favor of paclitaxel monotherapy (hazard ratio 1.80, 95% CI: 1.02 to 3.20; log-rank test P = 0.0409). It was decided to stop the trial early for futility. Median OS was also in favor of Arm A (20.7 months (95% CI: 16.4 to 26.7) versus 12.1 months (95% CI: 5.8 to 20.4) in Arm B. Clinical control was achieved in 28 patients (93.3%) in Arm A and in 21 patients 70.0% in Arm B. Overall response rate was met in 43.3% of patients in Arm A and in 40.0% in Arm B. Toxicities were increased in Arm B with higher rates of diarrhea, nausea, neutropenia, hand-foot skin reaction (HFSR) and anorexia, Grad 3 and 4 toxicities were rare.

Conclusions

In this pre-planned interim analysis, paclitaxel-sorafenib combination therapy was not found to be superior to paclitaxel monotherapy with regard to the primary end point, progression-free survival. The trial was therefore discontinued early. There was no indication of more favorable outcomes for combination therapy in secondary efficacy end points. As expected, the safety and toxicity profile of the combination therapy was less favorable compared to monotherapy. Overall, this trial did not demonstrate that adding sorafenib to second- or third-line paclitaxel provides any clinical benefit to patients with HER2-negative advanced or metastatic breast cancer. Cautious dosing using a sorafenib ramp up schedule might have contributed to negative results.

Trial registration

The study was registered at EudraCT (No 2009–018025-73) and retrospectively registered at Clinical trials.gov on March 17, 2011 (NCT01320111).
Literature
1.
2.
Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol. 2015;26(4):779–86.CrossRefPubMed
3.
Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, Coldman A, Gelmon KA, O'Reilly SE, Olivotto IA. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007;110(5):973–9.CrossRefPubMed
4.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34.CrossRefPubMed
5.
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.CrossRefPubMedPubMedCentral
6.
Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.CrossRefPubMed
7.
Carrick S, Parker S, Thornton CE, Ghersi D, Simes J, Wilcken N. Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. 2009;2:CD003372. doi:10.​1002/​14651858.​CD003372.​pub3.
8.
Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol. 2014;25(10):1871–88.CrossRefPubMedPubMedCentral
9.
Rossari JR, Metzger-Filho O, Paesmans M, Saini KS, Gennari A, de Azambuja E, Piccart-Gebhart M. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol. 2012;2012:417673.CrossRefPubMedPubMedCentral
10.
Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29(32):4286–93.CrossRefPubMed
11.
Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015;33(2):141–8.CrossRefPubMed
12.
Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of Eribulin Mesylate versus Capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a Taxane. J Clin Oncol. 2015;33(6):594–601.CrossRefPubMedPubMedCentral
13.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.CrossRefPubMed
14.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.CrossRefPubMed
15.
Ding Q, Huo L, Yang JY, Xia W, Wei Y, Liao Y, Chang CJ, Yang Y, Lai CC, Lee DF, et al. Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res. 2008;68(15):6109–17.CrossRefPubMedPubMedCentral
16.
Merz M, Komljenovic D, Zwick S, Semmler W, Bauerle T. Sorafenib tosylate and paclitaxel induce anti-angiogenic, anti-tumour and anti-resorptive effects in experimental breast cancer bone metastases. Eur J Cancer. 2011;47(2):277–86.CrossRefPubMed
17.
Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M, Flynn PJ, Fitch TR, Perez EA. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: north central cancer treatment group and Mayo Clinic trial N0336. J Clin Oncol. 2009;27(1):11–5.CrossRefPubMed
18.
Baselga J, Segalla JG, Roche H, Del Giglio A, Pinczowski H, Ciruelos EM, Filho SC, Gomez P, Van Eyll B, Bermejo B, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30(13):1484–91.CrossRefPubMed
19.
Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, Jain M, Ro SK, Lokker NA, Schwartzberg L. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49(2):312–22.CrossRefPubMed
20.
Cardoso F, Di LA, Lohrisch C, Bernard C, Ferreira F, Piccart MJ. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Ann Oncol. 2002;13(2):197–207.CrossRefPubMed
21.
Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.CrossRefPubMed
22.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.CrossRefPubMed
23.
Chen J, Tian CX, Yu M, Lv Q, Cheng NS, Wang Z, Wu X. Efficacy and safety profile of combining Sorafenib with chemotherapy in patients with HER2-negative advanced breast cancer: a meta-analysis. J Breast Cancer. 2014;17(1):61–8.CrossRefPubMedPubMedCentral
24.
Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist. 2010;15(1):85–92.CrossRefPubMedPubMedCentral
25.
Reig M, Torres F, Rodriguez-Lope C, Forner A, LL N, Rimola J, Darnell A, Rios J, Ayuso C, Bruix J. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61(2):318–24.CrossRefPubMed
26.
Loibl S, Rokitta D, Conrad B, Harbeck N, Wullner M, Warm M, Schwedler K, Gerber B, Schrader I, Eidtmann H, et al. Sorafenib in the treatment of early breast cancer: results of the neoadjuvant phase II study - SOFIA. Breast Care (Basel). 2014;9(3):169–74.CrossRef
27.
Baselga J, Costa F, Gomez H, Hudis CA, Rapoport B, Roche H, Schwartzberg LS, Petrenciuc O, Shan M, Gradishar WJ. A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial. Trials. 2013;14:228.CrossRefPubMedPubMedCentral
28.
J. Baselga C. Zamagni, P. Gomez, B. Bermejo, S. Nagai, B. Melichar, A. Chan, L. Mangel, J. Bergh, F.P. Costa, H.L. Gomez, W. Gradishar, C. Hudis, B. Rapoport, H. Roche, P. Maeda, L. Huang, J. Zhang, L.S. Schwartzberg: LBA8 - A phase III randomized, double-blind, trial comparing sorafenib plus capecitabine versus placebo plus capecitabine in the treatment of locally advanced or metastatic breast cancer. Annals of Oncology 2014, 25 (suppl_4): mdu438.5.
29.
Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.CrossRefPubMed
30.
Bolondi L, Craxi A, Trevisani F, Daniele B, Di Costanzo GG, Fagiuoli S, Camma C, Bruzzi P, Danesi R, Spandonaro F, et al. Refining sorafenib therapy: lessons from clinical practice. Future Oncol. 2015;11(3):449–65.CrossRefPubMed
31.
Dadu R, Waguespack SG, Sherman SI, Hu MI, Busaidy NL, Jimenez C, Habra MA, Ying AK, Bassett RL, Cabanillas ME. Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer. Oncologist. 2014;19(5):477–82.CrossRefPubMedPubMedCentral
32.
Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26(22):3743–8.CrossRefPubMed
33.
von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, et al. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1269–78.CrossRef
34.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.CrossRefPubMed
Metadata
Title
A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO)
Authors
Thomas Decker
Friedrich Overkamp
Siegfried Rösel
Arnd Nusch
Thomas Göhler
Martin Indorf
Jörg Sahlmann
Tanja Trarbach
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3492-1

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Chromosomal instability induced by increased BIRC5/Survivin levels affects tumorigenicity of glioma cells

Research article

A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt)- expressing tumour cells

Research article

Perceived stigmatization and its impact on quality of life - results from a large register-based study including breast, colon, prostate and lung cancer patients

Research article

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer

Research article

After accounting for competing causes of death and more advanced stage, do Aboriginal and Torres Strait Islander peoples with cancer still have worse survival? A population-based cohort study in New South Wales

Research article

Radiomics based analysis to predict local control and survival in hepatocellular carcinoma patients treated with volumetric modulated arc therapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits