Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

Abstract

Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with more aggressive disease and a poorer prognosis [[1]Ross J.S. Slodkowska E.A. Symmans W.F. Pusztai L. Ravdin P.M. Hortobagyi G.N. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.Oncologist. 2009; 14: 320-368https://doi.org/10.1634/theoncologist.2008-0230Crossref PubMed Scopus (904) Google Scholar]. For almost 20 years, trastuzumab, a humanised IgG1 monoclonal antibody that targets the extracellular domain of the HER2 protein, has been a key part of the initial treatment for HER2-positive metastatic breast cancer [[2]Kast K. Schoffer O. Link T. et al.Trastuzumab and survival of patients with metastatic breast cancer.Arch Gynecol Obstet. 2017; 296: 303-312https://doi.org/10.1007/s00404-017-4421-xCrossref PubMed Scopus (19) Google Scholar,[3]Dawood S. Broglio K. Buzdar A.U. Hortobagyi G.N. Giordano S.H. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review.J Clin Oncol. 2009; 28: 92-98https://doi.org/10.1200/JCO.2008.19.9844Crossref PubMed Scopus (595) Google Scholar]. More recently, the CLEOPATRA and EMILIA studies have established the use of dual HER2 blockade (pertuzumab and trastuzumab) alongside docetaxel as initial treatment followed by trastuzumab emtansine (T-DM1) at first extra-cranial disease progression. T-DM1 may also be prescribed as first-line treatment for those patients who progress on or within 6 months of adjuvant trastuzumab. These internationally accepted standards of care are available within the healthcare systems of England and the devolved nations [[4]Swain S.M. Baselga J. Kim S.-B. et al.Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.New Engl J Med. 2015; 372: 724-734https://doi.org/10.1056/NEJMoa1413513Crossref PubMed Scopus (1352) Google Scholar,[5]Verma S. Miles D. Gianni L. et al.Trastuzumab emtansine for HER2-positive advanced breast cancer.New Engl J Med. 2012; 367: 1783-1791https://doi.org/10.1056/NEJMoa1209124Crossref PubMed Scopus (2564) Google Scholar]. However, the optimal treatment after progression on T-DM1 remains more controversial, with data based on either retrospective analyses or small randomised studies that were undertaken in the era prior to the availability of dual anti-HER2 targeted treatment as well as T-DM1 [6Extra J.-M. Antoine E.C. Vincent-Salomon A. et al.Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the Observational Hermine Study.Oncologist. 2010; 15: 799-809https://doi.org/10.1634/theoncologist.2009-0029Crossref PubMed Scopus (94) Google Scholar, 7Mannocci A. De Feo E. de Waure C. et al.Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies.Tumori. 2010; 96: 385-391https://doi.org/10.1177/030089161009600302Crossref PubMed Scopus (30) Google Scholar, 8Petrelli F. Barni S. A pooled analysis of 2618 patients treated with trastuzumab beyond progression for advanced breast cancer.Clin Breast Cancer. 2013; 13: 81-87https://doi.org/10.1016/j.clbc.2012.11.008Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9Rayson D. Lutes S. Walsh G. et al.Trastuzumab beyond progression for HER2 positive metastatic breast cancer: progression-free survival on first-line therapy predicts overall survival impact.Breast J. 2014; 20: 408-413https://doi.org/10.1111/tbj.12284Crossref PubMed Scopus (9) Google Scholar, 10Waddell T. Kotsori A. Constantinidou A. et al.Trastuzumab beyond progression in HER2-positive advanced breast cancer: the Royal Marsden experience.Br J Cancer. 2011; 104: 1675-1679https://doi.org/10.1038/bjc.2011.138Crossref PubMed Scopus (18) Google Scholar, 11von Minckwitz G. Schwedler K. Schmidt M. et al.Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer.Eur J Cancer. 2011; 47: 2273-2281https://doi.org/10.1016/j.ejca.2011.06.021Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. Guidelines published by the National Institute for Health and Care Excellence (NICE) do not recommend trastuzumab either alone or in combination with further chemotherapy for patients with extra-cranial disease progression after T-DM1 [[12]NICEAdvanced breast cancer overview - NICE Pathways.https://pathways.nice.org.uk/pathways/advanced-breast-cancerDate accessed: October 9, 2019Google Scholar]. Despite the NICE guidance, it is apparent that some patients in the UK are being offered trastuzumab beyond progression (TBP). We undertook a survey to gain an insight into UK-wide prescribing of TBP, its funding and alternative treatment options. An online survey, advertised among national breast cancer groups, was available to prescribing breast oncologists from November 2019 to January 2020. We asked about the role of the prescriber, location, access to TBP, alternative regimens that may be used, availability of trials, whether the prescriber felt that they wanted access to TBP (if not available locally) and whether they would be willing to be contacted again if clarifications were required. If so, these were sought by e-mail correspondence. In total, 100 responses were received, of which 94 were evaluable. Reasons for exclusion included: duplicate entries, completion by health care professionals or patients who do not prescribe systemic anti-cancer therapy and missing responses that made interpretation not feasible. Of the 94 evaluable responses, 87 (92.5%) were from consultant oncologists, four (4.3%) were from associate specialists or staff grades, two (2.1%) were from speciality trainees in oncology and one (1.1%) was from a nurse prescriber. Responses came from a total of 62 National Health Service centres: 52 in England, five in Scotland, three in Wales, one in Northern Ireland and one from the Channel Islands. Thirty-six were university, teaching or cancer centres and 26 were district general hospitals. Overall, 32 (51.6%) centres were prescribing TBP, 29 (46.8%) were not and one (1.6%) had access to other anti-HER2 regimens (containing lapatinib, another anti-HER2 agent). When analysed by country: in England, 26 (50%) were prescribing TBP and 26 (50%) were not; in Scotland, two (40%) were and three (60%) were not; in Wales, two (66.6%) were and one (33.3%) had access to other HER2 regimens; the two respondents from Northern Ireland and the Channel Islands were both prescribing TBP. There was no difference in access by type of centre, with 17 of 36 (47.2%) university, teaching or oncology centres and 15 of 26 (57.7%) district general hospitals prescribing TBP. Access to clinical trials was variable at the time of survey, with 11 of 62 centres (17.7%) recruiting patients into trials of anti-HER2 agents in this setting. When asked about the funding of TBP, of the 41 respondents prescribing TBP, 23 (56.1%) cited a local funding arrangement, seven stated local clinical commissioning group funding (17.1%) and 11 (26.8%) were unsure where the source of funding came from. In those who could not prescribe TBP, a follow-up question asked what treatment they would offer next: 30 of 53 (56.6%) prescribe single agent chemotherapy, 13 (24.5%) would prescribe single agent chemotherapy or refer for a trial, three (5.7%) would refer straight for a trial, one (1.9%) would off either chemotherapy or endocrine therapy (if patients were oestrogen receptor positive), one (1.9%) would prescribe lapatinib and five (9.4%) respondents did not answer. A further question asked about the desire to have access to TBP in those who could not prescribe: 33 of 53 (62.3%) would like access, 13 (24.5%) were not sure, four did not (7.6%) and three (5.6%) did not answer. This survey highlights a wide variation in National Health Service practice in the healthcare systems of England and the devolved nations with regards to the use of TBP in HER2-positive breast cancer. Despite NICE guidance, 51.6% of centres continued to prescribe trastuzumab and, in those who could not prescribe TBP, most physicians would like access. The evidence for trastuzumab as part of third or subsequent lines of therapy is limited but is summarised in Table 1. The GBG26/BIG 3–05 trial found an overall survival benefit of continuing trastuzumab alongside chemotherapy compared with chemotherapy alone beyond progression of second-line therapy (median overall survival of the 88 patients who received third-line chemotherapy without anti-HER2 treatment was 13.3 months (95% confidence interval 10.2–14.7) months and in the 52 patients given third-line chemotherapy with anti-HER2 treatment, 18.8 months (95% confidence interval 12.9–24.8) months (hazard ratio 0.63, P = 0.02) [[11]von Minckwitz G. Schwedler K. Schmidt M. et al.Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer.Eur J Cancer. 2011; 47: 2273-2281https://doi.org/10.1016/j.ejca.2011.06.021Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar,[13]von Minckwitz G. du Bois A. Schmidt M. 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: 1999-2006https://doi.org/10.1200/JCO.2008.19.6618Crossref PubMed Scopus (601) Google Scholar]. Two recent studies with new anti-HER2 agents have shown the continued benefit of targeting the HER2 receptor in metastatic breast cancer. First, the phase III randomised HER2CLIMB study reported both a progression-free and overall survival benefit following progression on trastuzumab and pertuzumab and TDM-1 in HER2-positive patients treated with tucatinib in addition to trastuzumab and capecitabine compared with placebo, trastuzumab and capecitabine [[14]Murthy R.K. Loi S. Okines A. et al.Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.New Engl J Med. 2020; 382: 597-609https://doi.org/10.1056/NEJMoa1914609Crossref PubMed Scopus (555) Google Scholar]. Second, data from DESTINY-Breast01, a single-arm study of a novel antibody–drug conjugate Fam-trastuzumab deruxtecan, showed a response rate of 60.9% in a population who had received a median of six previous treatments for metastatic breast cancer [[15]Modi S. Saura C. Yamashita T. et al.Trastuzumab deruxtecan in previously treated HER2-positive breast cancer.New Engl J Med. 2020; 382: 610-621https://doi.org/10.1056/NEJMoa1914510Crossref PubMed Scopus (737) Google Scholar]. The activity of Fam-trastuzumab deruxtecan in patients progressing on TDM-1 is now being explored within the phase III randomised DESTINY-Breast02 trial (NCT03523585) – with the compactor arm being the investigators' choice of therapy (capecitabine plus trastuzumab or capecitabine plus lapatinib). In a similar patient population, the TULIP study is comparing another novel antibody–drug conjugate vic-trastuzumab duocarmazine (SYD985) with investigators' choice of therapy (trastuzumab plus either capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine) (NCT03262935). These completed and ongoing trials use trastuzumab in combination with cytotoxic chemotherapy as a control arm. This ‘standard of care’ [[13]von Minckwitz G. du Bois A. Schmidt M. 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: 1999-2006https://doi.org/10.1200/JCO.2008.19.6618Crossref PubMed Scopus (601) Google Scholar] is consistent with the most recent ESO-ESMO consensus guidelines that recommend continuing trastuzumab in HER2-positive metastatic breast cancer beyond progression on T-DM1 [[16]Cardoso F. Senkus E. Costa A. et al.4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4).Ann Oncol. 2018; 29: 1634-1657https://doi.org/10.1093/annonc/mdy192Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar].Table 1Completed or ongoing studies showing an improvement in progression-free or overall survival in advanced human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)TrialsRegimensSettingResultsReference/trial numberGBG26/BIG 3-05Trastuzumab and chemotherapy versus chemotherapy aloneThird-line MBCOverall survival: 18.8 versus 13.3 months. Hazard ratio 0.63, P = 0.02[[11]von Minckwitz G. Schwedler K. Schmidt M. et al.Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer.Eur J Cancer. 2011; 47: 2273-2281https://doi.org/10.1016/j.ejca.2011.06.021Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar,[13]von Minckwitz G. du Bois A. Schmidt M. 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: 1999-2006https://doi.org/10.1200/JCO.2008.19.6618Crossref PubMed Scopus (601) Google Scholar]HER2CLIMBEither tucatinib or placebo in combination with trastuzumab and capecitabineAdvanced MBC post-trastuzumab, pertuzumab and trastuzumab emtansinePFS (1 year) 33.1% versus 12.3%. Hazard ratio for disease progression or death, 0.54, P < 0.001.Overall survival (2 years) 44.9% versus 26.6%. Hazard ratio 0.66, P = 0.005[[14]Murthy R.K. Loi S. Okines A. et al.Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.New Engl J Med. 2020; 382: 597-609https://doi.org/10.1056/NEJMoa1914609Crossref PubMed Scopus (555) Google Scholar]DESTINY-Breast01Fam-trastuzumab deruxtecan (DS-8201)Single-arm phase II, advanced MBC, median six lines of previous treatmentResponse rate: 60.9%, median PFS 16.4 months[[15]Modi S. Saura C. Yamashita T. et al.Trastuzumab deruxtecan in previously treated HER2-positive breast cancer.New Engl J Med. 2020; 382: 610-621https://doi.org/10.1056/NEJMoa1914510Crossref PubMed Scopus (737) Google Scholar]DESTINY-Breast02Fam-trastuzumab deruxtecan (DS-8201) versus capecitabine plus trastuzumab or capecitabine plus lapatinibPhase IIResults awaitedNCT03523585TULIPvic-trastuzumab duocarmazine (SYD985) versus investigators' choice of therapy (trastuzumab plus either capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine)Phase IIResults awaitedNCT03262935PFS, progression-free survival. Open table in a new tab PFS, progression-free survival. Our survey results show a clear desire amongst UK oncologists to prescribe TBP and, despite NICE guidance, many centres are accessing trastuzumab for their patients. Consistent and up to date clinical practice guidance, to ensure equitable access to treatment, is needed to take into account both the falling of cost of generic trastuzumab and the recent evidence from both HER2CLIMB and DESTINY-Breast01 that suggest a biological rationale for it's continued use. Additionally, this survey highlights issues related to access to novel anti-HER2 agents within clinical trials across the UK, with only small minority of centres having this option available for patients. Although this study focused on trastuzumab, it is also apparent that there are disparities of access across the UK in accessing other systemic therapies for breast cancer including pertuzumab (not available adjuvantly in Scotland), lapatinib (only available in Wales) and single-agent fulvestrant (only available in Scotland and Northern Ireland) suggesting that a wider review of how decisions to fund and enable access to systemic therapies in advanced breast cancer is needed. T. Robinson has received educational grants from Daiichi-Sankyo and Amgen to attend educational workshops. He is currently a recipient of grants from the Academy of Medical Sciences (Starter Grant for Clinical Lecturers) and a National Institute for Health Research (NIHR) Academic Clinical Lectureship. C. Palmieri has received travel grants and honorarium for attending advisory boards from Roche.