Efficacy of trastuzumab emtansine (T-DM1) and lapatinib after dual HER2 inhibition with trastuzumab and pertuzumab in patient with metastatic breast cancer: Retrospective data from a French multicenter real-life cohort

Fabien Moinard-Butot, Caroline Saint-Martin, Carole Pflumio, Matthieu Carton, William Jacot, Paul-Henri Cottu, Véronique Diéras, Florence Dalenc, Anthony Goncalves, Marc Debled, Anne Patsouris, Marie-Ange Mouret-Reynier, Laurence Vanlemmens, Marianne Leheurteur, George Emile, Jean-Marc Ferrero, Isabelle Desmoulins, Lionel Uwer, Jean-Christophe Eymard, Bianca Cheaib, Coralie Courtinard, Thomas Bachelot, Michaël Chevrot, Thierry Petit, Fabien Moinard-Butot, Caroline Saint-Martin, Carole Pflumio, Matthieu Carton, William Jacot, Paul-Henri Cottu, Véronique Diéras, Florence Dalenc, Anthony Goncalves, Marc Debled, Anne Patsouris, Marie-Ange Mouret-Reynier, Laurence Vanlemmens, Marianne Leheurteur, George Emile, Jean-Marc Ferrero, Isabelle Desmoulins, Lionel Uwer, Jean-Christophe Eymard, Bianca Cheaib, Coralie Courtinard, Thomas Bachelot, Michaël Chevrot, Thierry Petit

Abstract

Purpose: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies.

Methods: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine.

Results: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS.

Conclusion: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.

Keywords: Dual HER2 blockade; Lapatinib; Metastatic breast cancer; Overall survival; Progression-free survival; T-DM1.

Conflict of interest statement

T.P. reports grants from Pfizer, Novartis, AstraZeneca, Lilly, and Pierre Fabre, but which were unrelated to the submitted work. C.P. reports board from Lilly and non-financial support from Novartis, Pfizer, Mundi Pharma, but which were unrelated to the submitted work. T.B. reports grants, personal fees and non-financial support from Novartis, Pfizer and AstraZeneca; personal fees from Seattle Genetics and personal fees and non-financial support from Roche. W.J. reports personal fees and non-financial support from Eisai, Novartis, Roche, Pfizer and Lilly; grants, personal fees and non-financial support from AstraZeneca; personal fees from MSD; non-financial support from Chugai. M.-A.M.-R. reports other from Novartis, Lilly, Pfizer, Roche, Pierre Fabre and MSD, outside the submitted work. F.D. reports boards from Novartis, Lilly, Pfizer and AstraZeneca. C.C. reports grants from Pfizer, Roche, MSD, AstraZeneca, Eisai and Daiichi. A.G. reports non-financial support from Roche, Novartis, AstraZeneca and Pfizer. PC reports grants from Pfizer and Novartis, personal fees from Pfizer and Eli-Lilly, and non-financial support from Pfizer, outside the submitted work. The other authors declare that they have no conflict of interest to disclose.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Flow chart: cohort A and B.
Fig. 2
Fig. 2
A. Cohort A: Progression-free survival. B. Cohort A: Progression-free survival according to previous-line duration, C. Cohort A: Progression-free survival according to HER2 status.
Fig. 3
Fig. 3
A. Cohort B: Progression-free survival. B. Cohort B: Progression-free survival according to previous-line duration.

References

    1. Grinda T., Antoine A., Jacot W., Blaye C., Cottu P.-H., Diéras V., Dalenc F., Gonçalves A., Debled M., Patsouris A., et al. Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort. ESMO Open. 2021;6:100114. doi: 10.1016/j.esmoop.2021.100114.
    1. Cameron D., Casey M., Oliva C., Newstat B., Imwalle B., Geyer C.E. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncol. 2010;15:924–934. doi: 10.1634/theoncologist.2009-0181.
    1. Verma S., Miles D., Gianni L., Krop I.E., Welslau M., Baselga J., Pegram M., Oh D.-Y., Diéras V., Guardino E., et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–1791. doi: 10.1056/NEJMoa1209124.
    1. Swain S.M., Baselga J., Kim S.-B., Ro J., Semiglazov V., Campone M., Ciruelos E., Ferrero J.-M., Schneeweiss A., Heeson S., 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. Swain S.M., Miles D., Kim S.-B., Im Y.-H., Im S.-A., Semiglazov V., Ciruelos E., Schneeweiss A., Loi S., Monturus E., et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519–530. doi: 10.1016/S1470-2045(19)30863-0.
    1. Pérol D., Robain M., Arveux P., Mathoulin-Pélissier S., Chamorey E., Asselain B., Berchery D., Gourgou S., Breton M., Delaine-Clisant S., et al. The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the epidemiological Strategy and medical Economics (ESME) BMJ Open. 2019;9 doi: 10.1136/bmjopen-2018-023568.
    1. Goldberg M., Chevalier A., Leclerc A., Lesieur S. Banque de données en santé publique; 2007. Recommandations de déontologie et bonnes pratiques en épidémiologie. - Résultats de votre recherche.
    1. Guidelines for good pharmacoepidemiology practices (GPP) - International Society for Pharmacoepidemiology. Available online.
    1. Recommendations for the immunohistochemistry of the hormonal receptors on paraffin sections in breast cancer. Update 1999. Group for Evaluation of Prognostic Factors using Immunohistochemistry in Breast Cancer (GEFPICS-FNCLCC) Ann Pathol. 1999;19:336–343.
    1. Wolff A.C., Hammond M.E.H., Schwartz J.N., Hagerty K.L., Allred D.C., Cote R.J., Dowsett M., Fitzgibbons P.L., Hanna W.M., Langer A., et al. American society of clinical oncology/college of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43. doi: 10.5858/2007-131-18-ASOCCO.
    1. Wolff A.C., Hammond M.E.H., Hicks D.G., Dowsett M., McShane L.M., Allison K.H., Allred D.C., Bartlett J.M.S., Bilous M., Fitzgibbons P., 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. Wolff A.C., Hammond M.E.H., Allison K.H., Harvey B.E., Mangu P.B., Bartlett J.M.S., Bilous M., Ellis I.O., Fitzgibbons P., Hanna W., et al. Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American Pathologists clinical practice guideline focused update. Arch Pathol Lab Med. 2018;142:1364–1382. doi: 10.5858/arpa.2018-0902-SA.
    1. Diéras V., Miles D., Verma S., Pegram M., Welslau M., Baselga J., Krop I.E., Blackwell K., Hoersch S., Xu J., et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:732–742. doi: 10.1016/S1470-2045(17)30312-1.
    1. Dzimitrowicz, H.; Berger, M.; Vargo, C.; Hood, A.; Abdelghany, O.; Raghavendra, A.S.; Tripathy, D.; Valero, V.; Hatzis, C.; Pusztai, L.; et al. T-DM1 activity in metastatic human epidermal growth factor receptor 2–positive breast cancers that received prior therapy with trastuzumab and pertuzumab. J Clin Oncol 8.
    1. Conte B., Fabi A., Poggio F., Blondeaux E., Dellepiane C., D'Alonzo A., Buono G., Arpino G., Magri V., Naso G., et al. T-DM1 efficacy in patients with HER2-positive metastatic breast cancer progressing after a taxane plus pertuzumab and trastuzumab: an Italian multicenter observational study. Clin Breast Cancer. 2019 doi: 10.1016/j.clbc.2019.09.001.
    1. Noda-Narita S., Shimomura A., Kawachi A., Sumiyoshi-Okuma H., Sudo K., Shimoi T., Noguchi E., Yonemori K., Shimizu C., Fujiwara Y., et al. Comparison of the efficacy of trastuzumab emtansine between patients with metastatic human epidermal growth factor receptor 2-positive breast cancers previously treated with combination trastuzumab and pertuzumab and with trastuzumab only in Japanese population. Breast Cancer. 2019;26:492–498. doi: 10.1007/s12282-019-00949-4.
    1. Baselga J., Lewis Phillips G.D., Verma S., Ro J., Huober J., Guardino A.E., Samant M.K., Olsen S., de Haas S.L., Pegram M.D. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res. 2016;22:3755–3763. doi: 10.1158/1078-0432.CCR-15-2499.
    1. Kim S.-B., Wildiers H., Krop I.E., Smitt M., Yu R., Lysbet de Haas S., Gonzalez-Martin A. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. Treatment of physician's choice in previously treated HER2-positive advanced breast cancer. Int J Cancer. 2016;139:2336–2342. doi: 10.1002/ijc.30276.
    1. Seol H., Lee H.J., Choi Y., Lee H.E., Kim Y.J., Kim J.H., Kang E., Kim S.-W., Park S.Y. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol. 2012;25:938–948. doi: 10.1038/modpathol.2012.36.
    1. Brunelli M., Manfrin E., Martignoni G., Miller K., Remo A., Reghellin D., Bersani S., Gobbo S., Eccher A., Chilosi M., et al. Genotypic intratumoral heterogeneity in breast carcinoma with HER2/Neu amplification: evaluation according to ASCO/CAP criteria. Am J Clin Pathol. 2009;131:678–682. doi: 10.1309/AJCP09VUTZWZXBMJ.
    1. Martin M., Bonneterre J., Geyer C.E., Ito Y., Ro J., Lang I., Kim S.-B., Germa C., Vermette J., Wang K., et al. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer. 2013;49:3763–3772. doi: 10.1016/j.ejca.2013.07.142.
    1. Takano T., Tsurutani J., Takahashi M., Yamanaka T., Sakai K., Ito Y., Fukuoka J., Kimura H., Kawabata H., Tamura K., 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. Saura, C.; Oliveira, M.; Feng, Y.-H.; Dai, M.-S.; Chen, S.-W.; Hurvitz, S.A.; Kim, S.-B.; Moy, B.; Delaloge, S.; Gradishar, W.; et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol 38, 23.
    1. Tarantino P., Prat A., Cortes J., Cardoso F., Curigliano G. Third-line treatment of HER2-positive advanced breast cancer: from No standard to a pandora's box. Biochim Biophys Acta Rev Cancer. 2021;1875:188487. doi: 10.1016/j.bbcan.2020.188487.
    1. DESTINY Breast03 second-line trastuzumab deruxtecan for metastatic HER2-positive breast cancer. The ASCO Post Available online.
    1. Curigliano G., Mueller V., Borges V., Hamilton E., Hurvitz S., Loi S., Murthy R., Okines A., Paplomata E., Cameron D., et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33:321–329. doi: 10.1016/j.annonc.2021.12.005.
    1. Lin N.U., Borges V., Anders C., Murthy R.K., Paplomata E., Hamilton E., Hurvitz S., Loi S., Okines A., Abramson V., et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38:2610–2619. doi: 10.1200/JCO.20.00775.
    1. Le parcours Du Médicament en France n.d. .

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe