INTRODUCTION: Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that has progressed on endocrine therapy. Metronomic administration may offer a better balance of efficacy and safety than standard regimens, but data from previous trials are scarce. METHODS: In this open-label, multicenter, phase II trial, patients were randomized to oral vinorelbine administered on a metronomic (50 mg three times weekly) or weekly (60 mg/m2 in cycle 1, increasing to 80 mg/m2 if well tolerated) schedule. Treatment was continued until disease progression or intolerance. The primary endpoint was disease control rate (DCR, the proportion of patients with a best overall confirmed response of CR, PR, or stable disease lasting 6 months or more). RESULTS: One-hundred sixty-three patients were randomized and treated. The DCR was 63.4% (95% confidence interval [CI]: 52.0-73.8) with metronomic vinorelbine and 72.8% (95% CI: 61.8-82.1) with weekly vinorelbine. Weekly vinorelbine was also associated with longer progression-free survival (5.6 vs 4.0 months) and overall survival (26.7 vs 22.3 months) than metronomic vinorelbine, but was associated with more adverse events. CONCLUSIONS: In this randomized phase II trial, single-agent metronomic oral vinorelbine was effective and well tolerated as first-line chemotherapy for patients with HR-positive/HER2-negative ABC. Formal comparisons are not done in this phase II study and one can simply observe that confidence intervals of all endpoints overlap. When deciding for a chemotherapy after failure of endocrine therapy and CDK 4/6 inhibitors, oral vinorelbine might be an option to be given with either schedule. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2014-003860-19.

Department of Obstetrics and Gynecology Klinikum Rechts der Isar Technische Universität München Ismaninger Straße 22 81675 Munich Germany

Department of Obstetrics and Gynecology Medical University of Graz Auenbruggerplatz 15 8036 Graz Austria

Hematology and Oncology Department AOU Policlinico di Modena Via del Pozzo 71 41125 Modena Italy

Medical Oncology Department Institut de Cancérologie des HCL 165 chemin du Grand Revoyet 69495 Pierre Bénite and Université de Lyon Lyon France

Oncology Department Centre Jean Bernard 9 rue Beauverger 72015 Le Mans France

Oncology Department Centrum Onkologii Ziemi Lubelskiej Ul Jaczewskiego 7 20 090 Lublin Poland

Oncology Department Centrum Terapii Wspolczesnej Ul Kopcinskiego 21 90 242 Łódź Poland

Oncology Department Hospital Clinic i Provincial de Barcelona 170 Esc 2 pl 5 08036 Barcelona Spain

Oncology Department Hospital Juan Ramón Jiménez C Ronda Norte s n 21005 Huelva Spain

Oncology Department Hospital Universitario Arnau De Vilanova Avenida Alcalde Rovira Roure 80 25198 Lleida Spain

Oncology Department Hospital Universitario Ramón y Cajal Carretera De Colmenar Viejo km 9 1 28034 Madrid Spain

Oncology Department Instituto Portugues de Oncologia do Porto Francisco Gentil EPE Rua Dr António Bernardino de Almeida 4200 072 Porto Portugal

Oncology Department Masakikuv Oncologicky Ustav Zluty Kopek 7 656 53 Brno Czech Republic

Oncology Department Petz Aladár County Hospital Vasvári Pál u 2 4 9024 Győr Hungary

Oncology Department SC Oncolab SRL Str Bujorului Nr 7 200385 Craiova Romania

Phase 1 Clinical Research Unit ASST Monza via Pergolesi 33 20052 Monza Italy; Medical Oncology University of Milano Bicocca Piazza dell'Ateneo Nuovo 1 20126 Milan Italy

Pierre Fabre Medicament Medical and Patient Consumer Department 33 Av Emile Zola 92100 Boulogne Billancourt France

See more in PubMed

Cardoso F., Paluch-Shimon S., Senkus E., Curigliano G., Aapro M.S., André F., et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann Oncol. 2020;31:1623–1649. doi: 10.1016/j.annonc.2020.09.010. PubMed DOI PMC

Jassem J., Ramlau R., Karnicka-Młodkowska H., Krawczyk K., Krzakowski M., Zatloukal P., et al. A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients. Ann Oncol. 2001;12:1375–1381. doi: 10.1023/a:1012539225493. PubMed DOI

Freyer G., Delozier T., Lichinister M., Gedouin D., Bougnoux P., His P., et al. Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol. 2003;21:35–40. doi: 10.1200/jco.2003.09.057. PubMed DOI

Aapro M., Ruiz-Borrego M., Hegg R., Kukielka-Budny B., Morales S., Cinieri S., et al. Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial) Breast. 2019;45:7–14. doi: 10.1016/j.breast.2019.01.009. PubMed DOI

Gennari A., André F., Barrios C.H., Cortés J., de Azambuja E., DeMichele A., et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32:1475–1495. doi: 10.1016/j.annonc.2021.09.019. PubMed DOI

Kerbel R.S., Kamen B.A. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–436. doi: 10.1038/nrc1369. PubMed DOI

Addeo R., Sgambato A., Cennamo G., Montella L., Faiola V., Abbruzzese A., et al. Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer. 2010;10:301–306. doi: 10.3816/CBC.2010.n.039. PubMed DOI

Cazzaniga M.E., Biganzoli L., Cortesi L., De Placido S., Donadio M., Fabi A., et al. Treating advanced breast cancer with metronomic chemotherapy: what is known, what is new and what is the future? OncoTargets Ther. 2019;12:2989–2997. doi: 10.2147/ott.S189163. PubMed DOI PMC

Cazzaniga M.E., Cordani N., Capici S., Cogliati V., Riva F., Cerrito M.G. Metronomic chemotherapy. Cancers (Basel) 2021;13:2236. doi: 10.3390/cancers13092236. PubMed DOI PMC

Muller P.Y., Milton M.N. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov. 2012;11:751–761. doi: 10.1038/nrd3801. PubMed DOI

Briasoulis E., Pappas P., Puozzo C., Tolis C., Fountzilas G., Dafni U., et al. Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res. 2009;15:6454–6461. doi: 10.1158/1078-0432.Ccr-09-0970. PubMed DOI

Rajdev L., Negassa A., Dai Q., Goldberg G., Miller K., Sparano J.A. Phase I trial of metronomic oral vinorelbine in patients with advanced cancer. Cancer Chemother Pharmacol. 2011;68:1119–1124. doi: 10.1007/s00280-011-1580-5. PubMed DOI

Briasoulis E., Aravantinos G., Kouvatseas G., Pappas P., Biziota E., Sainis I., et al. Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a Hellenic Cooperative Oncology Group clinical translational study. BMC Cancer. 2013;13:263. doi: 10.1186/1471-2407-13-263. PubMed DOI PMC

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10. doi: 10.1016/0197-2456(89)90015-9. PubMed DOI

Santos K.D., Lien K., Georgsdottir S., Sivanathan L., Emmenegger U. In: Metronomic chemotherapy: pharmacology and clinical applications. Bocci G., Francia G., editors. Springer Berlin Heidelberg; Berlin, Heidelberg: 2014. Adverse side effects associated with the use of low-dose metronomic chemotherapy; pp. 263–279.

Brems-Eskildsen A.S., Linnet S., Danø H., Luczak A., Vestlev P.M., Jakobsen E.H., et al. Metronomic treatment of vinorelbine with oral capecitabine is tolerable in the randomized phase 2 study XeNa including patients with HER2 non-amplified metastatic breast cancer. Acta Oncol. 2021;60:157–164. doi: 10.1080/0284186x.2020.1851045. PubMed DOI

Cazzaniga M.E., Vallini I., Montagna E., Amoroso D., Berardi R., Butera A., et al. Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study. Breast Cancer Res Treat. 2021;190:415–424. doi: 10.1007/s10549-021-06375-5. PubMed DOI PMC

Liu C.T., Hsieh M.C., Su Y.L., Hung C.M., Pei S.N., Liao C.K., et al. Metronomic vinorelbine is an excellent and safe treatment for advanced breast cancer: a retrospective, observational study. J Cancer. 2021;12:5355–5364. doi: 10.7150/jca.60682. PubMed DOI PMC

Wang Z., Liu J., Ma F., Wang J., Luo Y., Fan Y., et al. Safety and efficacy study of oral metronomic vinorelbine combined with trastuzumab (mNH) in HER2-positive metastatic breast cancer: a phase II trial. Breast Cancer Res Treat. 2021;188:441–447. doi: 10.1007/s10549-021-06216-5. PubMed DOI PMC

Montagna E., Pagan E., Cancello G., Sangalli C., Bagnardi V., Munzone E., et al. The prolonged clinical benefit with metronomic chemotherapy (VEX regimen) in metastatic breast cancer patients. Anti Cancer Drugs. 2022;33:e628–e634. doi: 10.1097/CAD.0000000000001209. PubMed DOI

Krajnak S., Decker T., Schollenberger L., Rosé C., Ruckes C., Fehm T., et al. Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2- breast cancer resistant to endocrine therapy: VinoMetro-AGO-B-046. J Cancer Res Clin Oncol. 2021;147:3391–3400. doi: 10.1007/s00432-021-03599-2. PubMed DOI PMC

Adamo B., Bellet M., Paré L., Pascual T., Vidal M., Pérez Fidalgo J.A., et al. Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial. Breast Cancer Res. 2019;21:108. doi: 10.1186/s13058-019-1195-z. PubMed DOI PMC

Camerini A., Morabito A., Montanino A., Bernabe R., Grossi F., Ramlau R., et al. Metronomic oral vinorelbine in previously untreated advanced non-small-cell lung cancer patients unfit for platinum-based chemotherapy: results of the randomized phase II Tempo Lung trial. ESMO Open. 2021;6 doi: 10.1016/j.esmoop.2021.100051. PubMed DOI PMC

Krajnak S., Battista M.J., Hasenburg A., Schmidt M. Metronomic chemotherapy for metastatic breast cancer. Oncol Res Treat. 2021;45:12–17. doi: 10.1159/000520236. PubMed DOI

Langkjer S.T., Kenholm J., Jensen J.D., Wedervang K., Brixen A.T., Grunnet M., et al. The NAME trial: a direct comparison of classical oral navelbine versus metronomic navelbine in metastatic breast cancer. Future Oncol. 2019;15:2561–2569. doi: 10.2217/fon-2019-0124. PubMed DOI

Munzone E., Regan M.R., Cinieri S., Montagna E., Orlando, Shi R L., et al. Efficacy of metronomic oral vinorelbine, cyclophosphamide, and capecitabine vs weekly intravenous paclitaxel in patients with estrogen receptor-positive, ERBB2-negative metastatic breast cancer: final results from the phase 2 METEORA-II randomized clinical trial. JAMA Oncol. 2023 Sep 1;9(9):1267–2569. doi: 10.1001/jamaoncol.2023.2150. PubMed DOI PMC