Effect of early adverse events resulting in ado-trastuzumab emtansine dose adjustments on survival outcomes of HER2+ advanced breast cancer patients
Ado-trastuzumab emtansine (T-DM1) treatment in HER2+ advanced breast cancer patients is generally well tolerated, but when adverse events occur dose adjustments may be required. This study evaluated the impact of early adverse events requiring T-DM1 dose interruptions or reductions on overall survival (OS) and progression-free survival (PFS) in HER2+ advanced metastatic breast cancer patients in the clinical trials EMILIA and TH3RESA.
Patients and methods
The study included 893 participants initiated on T-DM1 treatment. A landmark approach set at 4 months was used to evaluate the association between early adverse events requiring T-DM1 dose interruptions or reductions and OS/PFS. Cox proportional hazard analysis modeled the association between events requiring T-DM1 dose interruptions or reductions and OS/PFS. Associations were reported as hazard ratios with 95% confidence intervals.
Adverse events requiring T-DM1 dose interruptions or reductions within the first 4 months of treatment were not significantly associated with OS (hazard ratio (HR) [95% CI]: dose interrupted = 1.15 [0.85–1.55]; dose reduced = 0.75 [0.49–1.14]; P = 0.214) nor PFS (hazard ratio (HR) [95% CI]: dose interrupted = 1.13 [0.87–1.48]; dose reduced = 0.90 [0.62–1.31]; P = 0.534).
The occurrence of early adverse events requiring T-DM1 dose interruptions or reductions do not appear to be associated with altered long-term OS or PFS within a pooled analysis of data from EMILIA and TH3RESA.
KeywordsAdo-trastuzumab emtansine Adverse events Dose adjustment Survival Advanced breast cancer
Research undertaken with the financial support of Cancer Council South Australia’s Beat Cancer Project on behalf of its donors and the State Government through the Department of Health (Grant ID: 1159924 and 1127220). Ashley M. Hopkins is an early career researcher funded by a Fellowship from the National Breast Cancer Foundation, Australia (PF-17-007). Ross A. McKinnon is supported by the Cancer Council’s Beat Cancer Project with support from the South Australian Department of Health.
All authors were involved in literature search, design, analysis, interpretation and manuscript preparation for this project.
Compliance with ethical standards
Conflict of interest
Michael J. Sorich and Andrew Rowland report investigator-initiated project grants from Pfizer, outside the scope of the submitted work. Ashley M. Hopkins, Ethan Tang, Ross A. McKinnon have no conflicts of interest to disclose.
Secondary analysis of anonymized participant-level trial data was approved by Southern Adelaide Clinical Human Research Ethics Committee.
- 4.Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortés J, Curigliano G, Diéras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP (2018) 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 4)†. Ann Oncol 29(8):1634–1657. https://doi.org/10.1093/annonc/mdy192 CrossRefGoogle Scholar
- 5.Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L (2017) 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 18(6):732–742. https://doi.org/10.1016/S1470-2045(17)30312-1 CrossRefGoogle Scholar
- 6.Krop IE, Kim S-B, Martin AG, LoRusso PM, Ferrero J-M, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H (2017) Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18(6):743–754. https://doi.org/10.1016/S1470-2045(17)30313-3 CrossRefGoogle Scholar
- 7.Krop IE, Kim S-B, González-Martín A, LoRusso PM, Ferrero J-M, Smitt M, Yu R, Leung ACF, Wildiers H (2014) 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 15(7):689–699. https://doi.org/10.1016/S1470-2045(14)70178-0 CrossRefGoogle Scholar
- 9.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92(3):205–216. https://doi.org/10.1093/jnci/92.3.205 CrossRefGoogle Scholar
- 10.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefGoogle Scholar
- 13.Wang J, Song P, Schrieber S, Liu Q, Xu Q, Blumenthal G, Amiri Kordestani L, Cortazar P, Ibrahim A, Justice R, Wang Y, Tang S, Booth B, Mehrotra N, Rahman A (2014) Exposure–response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer. Clin Pharmacol Ther 95(5):558–564. https://doi.org/10.1038/clpt.2014.24 CrossRefGoogle Scholar
- 14.Roche (2019) Roche global policy on sharing of clinical study information. Roche. https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. Accessed 7 Jul 2019