Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16)

Sung Hoon Sim, In Hae Park, Kyung Hae Jung, Sung-Bae Kim, Jin-Hee Ahn, Kyung-Hun Lee, Seock-Ah Im, Young-Hyuck Im, Yeon Hee Park, Joohyuk Sohn, Yu Jung Kim, Suee Lee, Hee-Jun Kim, Yee Soo Chae, Kyong Hwa Park, Byung-Ho Nam, Keun Seok Lee, Jungsil Ro, Sung Hoon Sim, In Hae Park, Kyung Hae Jung, Sung-Bae Kim, Jin-Hee Ahn, Kyung-Hun Lee, Seock-Ah Im, Young-Hyuck Im, Yeon Hee Park, Joohyuk Sohn, Yu Jung Kim, Suee Lee, Hee-Jun Kim, Yee Soo Chae, Kyong Hwa Park, Byung-Ho Nam, Keun Seok Lee, Jungsil Ro

Abstract

Background: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments.

Methods: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks.

Results: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable.

Conclusions: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib.

Clinical trial registration: ClinicalTrials.gov number NCT01730677.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study flowchart
Fig. 2
Fig. 2
Survival analysis in the intention-to-treat (ITT) population. Kaplan–Meier curve for progression-free survival (PFS) (a) and overall survival (OS) (b) between lapatinib with vinorelbine (LV) and vinorelbine alone (V)
Fig. 3
Fig. 3
Subgroup analysis of 18-week progression-free survival (PFS). Hormone receptor negative, prior lapatinib response (CR or PR) and the last administration of lapatinib within 6 months favoured LV treatment but it did not show statistical significance

References

    1. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 2015;372:724–734. doi: 10.1056/NEJMoa1413513.
    1. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2006;355:2733–2743. doi: 10.1056/NEJMoa064320.
    1. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03-05 study. J. Clin. Oncol. 2009;27:1999–2006. doi: 10.1200/JCO.2008.19.6618.
    1. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 2010;28:1124–1130. doi: 10.1200/JCO.2008.21.4437.
    1. Network NCC. Breast cancer (version 1.2019). . Accessed April 22, 2019.
    1. Takano T, Tsurutani J, Takahashi M, Yamanaka T, Sakai K, Ito Y, et al. A randomized phase II trial of trastuzumab plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP. Breast. 2018;40:67–75. doi: 10.1016/j.breast.2018.04.010.
    1. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. 2013;31:3997–4013. doi: 10.1200/JCO.2013.50.9984.
    1. Rezai K, Urien S, Isambert N, Roche H, Dieras V, Berille J, et al. Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients. Cancer Chemother. Pharmacol. 2011;68:1529–1536. doi: 10.1007/s00280-011-1650-8.
    1. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase II trials and a proposal for phase II screening trials. J. Clin. Oncol. 2005;23:7199–7206. doi: 10.1200/JCO.2005.01.149.
    1. Park IH, Lee KS, Ro J. Effects of second and subsequent lines of chemotherapy for metastatic breast cancer. Clin. Breast Cancer. 2015;15:e55–62. doi: 10.1016/j.clbc.2014.09.001.
    1. Krop IE, Kim SB, Gonzalez-Martin A, LoRusso PM, Ferrero JM, Smitt M, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:689–699. doi: 10.1016/S1470-2045(14)70178-0.
    1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012;367:1783–1791. doi: 10.1056/NEJMoa1209124.
    1. Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 2009;27:5838–5847. doi: 10.1200/JCO.2009.22.1507.
    1. Tolaney SM, Krop IE. Mechanisms of trastuzumab resistance in breast cancer. Anti-cancer Agents Med. Chem. 2009;9:348–355. doi: 10.2174/1871520610909030348.
    1. Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8:215. doi: 10.1186/bcr1612.
    1. Sudhan DR, Schwarz LJ, Guerrero-Zotano A, Formisano L, Nixon MJ, Croessmann S, et al. Extended adjuvant therapy with neratinib plus fulvestrant blocks ER/HER2 crosstalk and maintains complete responses of ER(+)/HER2(+) breast cancers: implications to the ExteNET trial. Clin. Cancer Res. 2019;25:771–783. doi: 10.1158/1078-0432.CCR-18-1131.
    1. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers-role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13:R121. doi: 10.1186/bcr3067.
    1. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clinical Cancer Res. 2007;13:4909–4919. doi: 10.1158/1078-0432.CCR-07-0701.
    1. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–5887. doi: 10.1158/0008-5472.CAN-08-0380.
    1. Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–814. doi: 10.1038/onc.2008.432.
    1. Gori S, Montemurro F, Spazzapan S, Metro G, Foglietta J, Bisagni G, et al. Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer. Ann. Oncol. 2012;23:1436–1441. doi: 10.1093/annonc/mdr474.
    1. Park YH, Lee KH, Sohn JH, Lee KS, Jung KH, Kim JH, et al. A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial. Int. J. Cancer. 2018;143:3240–3247. doi: 10.1002/ijc.31651.
    1. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther. Adv. Med. Oncol. 2019;11:1758835919833519. doi: 10.1177/1758835919833519.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe